Glucagon (GCG) like peptide 1 (GLP-1) has emerged as a powerful player in regulating metabolism and a promising therapeutic target for various chronic diseases. This review delves into the physiological roles of GLP-1, exploring its impact on glucose homeostasis, insulin secretion, and satiety. We examine the compelling evidence supporting GLP-1 receptor agonists (GLP-1RAs) in managing type 2 diabetes (T2D), obesity, and other diseases. The intricate molecular mechanisms underlying GLP-1RAs are explored, including their interactions with pathways like extracellular signal-regulated kinase 1/2 (ERK1/2), activated protein kinase (AMPK), cyclic adenine monophosphate (cAMP), mitogen-activated protein kinase (MAPK), and protein kinase C (PKC). Expanding our understanding, the review investigates the potential role of GLP-1 in cancers. Also, microribonucleic acid (RNA) (miRNAs), critical regulators of gene expression, are introduced as potential modulators of GLP-1 signaling. We delve into the link between miRNAs and T2D obesity and explore specific miRNA examples influencing GLP-1R function. Finally, the review explores the rationale for seeking alternatives to GLP-1RAs and highlights natural products with promising GLP-1 modulatory effects.

Bariatric surgery, while effective for severe obesity, is often challenged by postoperative weight regain (WR), affecting 20-30% of patients. This review analyzes the mechanisms, risk factors, and management strategies for WR, emphasizing surgical considerations. WR is influenced by hormonal adaptations, including ghrelin rebound and leptin resistance, as well as metabolic adaptation, leading to reduced resting energy expenditure. Surgical factors, such as suboptimal technique, gastro-gastric fistulas, and stomach/anastomosis dilation, significantly contribute to WR. Specifically, inaccurate sleeve or pouch sizing, poorly calibrated anastomoses, and complications with gastric banding necessitate careful surgical planning and potential revision. Management strategies encompass lifestyle interventions (diet, exercise, behavioral therapy), pharmacotherapy (GLP-1 receptor agonists like liraglutide, semaglutide, and tirzepatide), and revisional surgery. Revisional procedures, including sleeve-to-bypass, bypass revision, sleeve-to-duodenal switch/SADI, and band removal with conversion to sleeve or bypass, address anatomical failures and enhance weight loss. Distinguishing surgical failure from patient nonadherence is crucial for appropriate intervention. Ultimately, a collaborative, multidisciplinary approach integrating these strategies optimizes long-term weight management and improves patient outcomes after bariatric surgery.

Tirzepatide is a novel drug for the treatment of type 2 diabetes mellitus and chronic weight management, and there is an urgent need to explore its safety profile. The FDA Adverse Event Reporting System (FAERS) database provides a reliable pathway for adverse event (AE) disproportionality analysis. Data regarding AEs registered in the FAERS between Q2 2022 and Q4 2023 were collected for this study. The reporting odds ratio (ROR) method was applied to analyse the association between tirzepatide use and the risk of developing AEs. The occurrence of ≥3 AEs with an ROR value 95% confidence interval (CI) lower limit >1 was considered to indicate statistical significance. Data on 638,153 AEs were collected from the FAERS database, and tirzepatide use was implicated for 8,096 of those AEs. A total of 98 preferred terms (PTs) were detected as positive signals for tirzepatide use. Frequently observed expected AEs included injection site pain, nausea, injection site haemorrhage, diarrhoea, and vomiting. Some unexpected AEs that were frequently observed included incorrect doses, off-label use, the administration of extra doses, an inappropriate schedule of product administration, and increased blood glucose. In this study, we identified potential novel and unexpected AE signals associated with tirzepatide use. Our findings confirm the importance of real-world disproportionality analysis in identifying the safety profile of new drugs, ultimately contributing to the safe clinical application of tirzepatide.

The use of gut-hormone receptors agonists as new therapeutic options for obesity and some of its related comorbidities, such as type 2 diabetes, has resulted in an unprecedented efficacy in the medical management of people living with obesity (PLWO). Appraisal of the safety of these drugs is of utmost importance considering the large number of PLWO, and the potentially long exposure to these pharmacotherapies. In this narrative review we summarize the evidence on the safety of liraglutide, semaglutide, and tirzepatide as derived from randomized clinical trials conducted in adults living with obesity. Additionally, the safety of these drugs is put into perspective with that of other drugs currently approved for the treatment of PLWO. Overall, the available data support a favorable efficacy versus safety balance for gut-hormone hormone receptor analogues in the treatment of these subjects. Nonetheless, it should be acknowledged that in the context of a chronic disease that has reached epidemic proportions, data from randomized clinical trials aimed primarily at proving the efficacy of these drugs may have been insufficient to unveil all the safety issues. Thus, continuous surveillance on the adverse effects of liraglutide, semaglutide, and tirzepatide is required as we use these drugs in a broader population than that represented in currently available clinical trials.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is currently a pressing public health issue associated with adverse outcomes such as cirrhosis, malignancy, transplantation, and mortality. Lifestyle modifications constitute the most effective and fundamental management approach, but they often pose challenges in sustaining long-term clinical benefits. Hence, there is a critical need to enhance our understanding through pharmacological management, which unfortunately remains limited. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as a leading treatment in the fields of diabetes and obesity, with recent preclinical and clinical studies indicating significant benefits in the management and treatment of MASLD. Our article begins by reviewing the beneficial therapeutic components of GLP-1RAs in MASLD. Subsequently, from a clinical research perspective, we concluded with the liver outcomes of current primary GLP-1RAs and co-agonists. Finally, we presented our insights on clinical concerns such as appropriate trial endpoints, management of comorbidities, and future developments. In conclusion, the benefits of GLP-1RAs in MASLD are promising, and background therapy involving metabolic modulation may represent one of the future therapeutic paradigms.

Diabetes mellitus (DM) is a significant risk factor for various cancers, with the impact of anti-diabetic therapies on cancer progression differing across malignancies. Among these therapies, metformin has gained attention for its potential anti-cancer effects, primarily through modulation of the AMP-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) pathway and the induction of autophagy. Beyond metformin, other conventional anti-diabetic treatments, such as insulin, sulfonylureas (SUs), pioglitazone, and dipeptidyl peptidase-4 (DPP-4) inhibitors, have also been examined for their roles in cancer biology, though findings are often inconclusive. More recently, novel medications, like glucagon-like peptide-1 (GLP-1) receptor agonists, dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) agonists, and sodium-glucose co-transporter-2 (SGLT-2) inhibitors, have revolutionized DM management by not only improving glycemic control but also delivering substantial cardiovascular and renal benefits. Given their diverse metabolic effects, including anti-obesogenic properties, these novel agents are now under meticulous investigation for their potential influence on tumorigenesis and cancer advancement. This review aims to offer a comprehensive exploration of the evolving landscape of glucose-lowering treatments and their implications in cancer biology. It critically evaluates experimental evidence surrounding the molecular mechanisms by which these medications may modulate oncogenic signaling pathways and reshape the tumor microenvironment (TME). Furthermore, it assesses translational research and clinical trials to gauge the practical relevance of these findings in real-world settings. Finally, it explores the potential of anti-diabetic medications as adjuncts in cancer treatment, particularly in enhancing the efficacy of chemotherapy, minimizing toxicity, and addressing resistance within the framework of immunotherapy.

Modern lifestyle diseases remain a persistent challenge in healthcare. Currently, about 422 million people worldwide are affected by diabetes, while 1 in 8 people are living with obesity. The development of glucagon-like peptide 1 receptor agonists (GLP-1RAs) has marked a significant milestone in treating these conditions. Interest in GLP-1RAs has grown due to evidence that, beyond their established role in diabetes management, these drugs influence other metabolic disorders. This is attributed to the fact that GLP-1 receptors are found in various healthy human tissues. However, a potential cause for concern is the expression of GLP-1 receptors in certain cancers. This review focuses on the most recent findings concerning the actions of GLP-1RAs, detailing their documented impact on the thyroid gland and pancreas. It addresses concerns about the long-term use of GLP-1RAs in relation to the development of pancreatitis, pancreatic cancer, and thyroid neoplasms by exploring the mechanisms and long-term effects in different patient subgroups and including data not discussed previously. This review was conducted through an examination of the literature available in the MedLine (PubMed) database, covering publications from 1978 to 10 May 2024. The collected articles were selected based on their relevance to studies of GLP-1 agonists and their effects on the pancreas and thyroid and assessed to meet the established inclusion criteria. The revised papers suggest that prolonged use of GLP-1RA could contribute to the formation of thyroid tumors and may increase the risk of acute inflammatory conditions such as pancreatitis, particularly in high-risk patients. Therefore, physicians should advise patients on the need for more frequent and detailed follow-ups.

GLP-1 receptor agonists provide multiple benefits for patients with type 2 diabetes. Nonetheless, there are also several significant adverse effects associated with these agents. A thorough understanding of both therapeutic and toxicological profiles of GLP-1 receptor agonists is crucial for appropriate utilization of this medication class. A literature search of PubMed and ClinicalTrials.gov was carried out to inform discussion on the topic.

This review article discusses the key advantages and disadvantages derived from the use of GLP-1 receptor agonists in the treatment of type 2 diabetes. Landmark trials which helped characterize the cardiovascular and renal benefits of GLP-1 receptor agonists are highlighted. We also discuss key studies still in progress and new formulations under investigation.

GLP-1 receptor agonists provide glycemic and complication-risk reduction benefits for individuals with type 2 diabetes. Current data suggests there is a lot of potential for further applications, even outside of type 2 diabetes management. It would be of particular interest to see the range of benefits conferred from GLP-1 receptor agonists in individuals without type 2 diabetes. Broader application of these medications could be expected given the ongoing development of new oral formulations and combination agents.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are commonly used for glucose lowering and weight-loss. However, their association with gastrointestinal cancer remains uncertain. This meta-analysis assesses the risk of gastrointestinal cancer in patients treated with GLP-1 RAs.

We searched Medline/PubMed, Embase, and Scopus databases from inception to November 15, 2023, for randomized controlled trials (RCTs) with at least 24 weeks of safety follow-up. Pooled risk ratios (RRs) were calculated using fixed- and random-effect models. Risk of bias was assessed using the revised Cochrane risk-of-bias tool, and certainty of evidence was determined using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework.

We included 90 RCTs with 124,791 participants, with an average follow-up of 3.1 years per participant. No significant association was found between GLP-1 RAs and the risk of any gastrointestinal cancer (RRrandom=0.99, 95 % CI: 0.86-1.13), or site-specific gastrointestinal cancers including biliary tract (RR=0.98, 0.54-1.78), colorectal (RR=1.13, 0.92-1.39), gallbladder (RR=1.32, 0.43-4.00), gastric (RR=0.88, 0.58-1.33), hepatic (RR=0.79, 0.51-1.21), oesophageal (RR=0.70, 0.38-1.28), pancreatic (RR=1.05, 0.77-1.43), and small intestine cancer (RR=0.78, 0.20-3.04). The corresponding absolute risk differences excluded important impacts on risk. Additional analyses, limited to placebo-controlled trials, high-dose studies, or those with a follow-up duration of ≥5 years, confirmed these findings. Risk of bias was generally low and the certainty of evidence was high for all outcomes.

This meta-analysis found no significant impact of GLP-1 RAs on gastrointestinal cancer risk. Long-term safety monitoring of these agents remains important.

CRD42023476762.

Glucagon-like peptide-1 receptor agonists (GLP-1-RAs) are a novel class of medications promising for treating type 2 diabetes mellitus (T2DM) and obesity-related conditions such as cardiovascular disease (CVD) and non-alcoholic fatty liver disease (NAFLD). This comprehensive literature review examines available research on these medications, focusing on their mechanisms of action, clinical effectiveness, safety profiles, and socioeconomic implications. A comprehensive search was performed using the PubMed, EMBASE, and Cochrane Library databases. Although initially developed for glucose management, these drugs have also demonstrated efficacy in promoting weight loss and reducing the risk of CVD. GLP-1-RAs function similarly to naturally occurring incretins. They stimulate insulin secretion in response to glucose levels, inhibit glucagon release, delay stomach emptying, and generate a sense of fullness via brain pathways. Head-to-head clinical studies have indicated that GLP-1-RAs outperform conventional antidiabetic medicines in terms of glycemic management and weight reduction. According to cardiovascular outcome studies, various drugs in this category have been found to reduce the frequency of severe adverse cardiovascular events. A common side effect is gastrointestinal toxicity, which can be mitigated by gradually increasing the dose. Personalized treatment is likely because the effectiveness, safety, and dose regimens of currently available GLP-1-RAs differ. GLP-1-RAs are a superior choice for patients with T2DM, especially those who already have CVD or require weight-control support. The high cost of these drugs creates hurdles to access and fair healthcare. Current research mainly focuses on increasing therapeutic uses and producing orally delivered medicines with greater potency and bioavailability. Integrating GLP-1-RAs into clinical practice can enhance patient outcomes and reduce the community burden of cardiometabolic disease.

Metabolic and bariatric surgery (MBS) is a potent intervention for addressing obesity-related medical conditions and achieving sustainable weight loss. Beyond its conventional role, MBS has demonstrated potential to serve as a transitional step for patients requiring various interventions. However, the implications of MBS in the context of neoplasia remain understudied.

To explore the feasibility of MBS as a possible attempt to reduce surgical and treatment risks in patients with benign tumors or low-grade cancers.

Multicenter review from twelve tertiary referral centers spanning 8 countries.

A retrospective review of patients with a diagnosis of primary neoplasia, deemed inoperable or high-risk due to obesity, and receiving primary MBS prior to neoplastic therapy. Data encompassed baseline characteristics, neoplasia characteristics, MBS outcomes, and neoplastic therapy outcomes.

Thirty-seven patients (median age 52 years, 75.7% female, median BMI of 49.1 kg/m2) were included. There were 9 distinct organs of origin of primary neoplasia, with the endometrium (43.2%) being the most common, followed by the pancreas, colon, kidney and breast. Sleeve gastrectomy (SG) was the most commonly performed MBS procedure (78.4%), with no MBS-related complications or mortalities reported over an average of 4.3 ± 3.9 years. Thirty-one patients (83.8%) eventually underwent neoplastic surgery, with a mean BMI decrease from 49.9 kg/m2 to 39.7 kg/m2 at surgery over an average of 5.8 ± 4.8 months. There were 2 (6.7%) documented mortalities associated with neoplastic surgical intervention.

This study highlights the potential feasibility of employing MBS prior to neoplastic therapy in patients with low-grade, less aggressive neoplasms in the context of obesity. This underscores the importance of providing a personalized, case-to-case multidisciplinary approach in the management of these patients.

A man, in his 30s, with a history of obesity and hypothyroidism planned to begin taking a new Glucagon-like peptide-1 (GLP-1) agonist for weight loss. As these medications have been associated with C-cell hyperplasia, a calcitonin level was checked as evaluation prior to starting the drug. This returned at 131 pg/mL (upper limit of normal<10 pg/mL), and a subsequent carcinoembryonic antigen was 5.2 ng/mL (ref<3 ng/mL). Thyroid ultrasound was performed and demonstrated bilateral subcentimeter nodules. After total thyroidectomy, final pathology demonstrated bilateral 0.8 cm medullary thyroid carcinoma. Genetic testing revealed a NM_020975.6: c.1826G > A; p.Cys609Tyr. germline RET mutation, confirming the diagnosis of multiple endocrine neoplasia 2 syndrome. The patient recovered well from treatment. His first-degree relatives also underwent genetic testing. This case represents a surprising diagnosis of familial multiple endocrine neoplasia 2A prior to starting a Glucagon-like peptide-1 agonist.

Remedies for the treatment of obesity date to Hippocrates, when patients with obesity were directed to "reduce food and avoid drinking to fullness" and begin "running during the night." Similar recommendations have been repeated ever since, despite the fact that they are largely ineffective. Recently, highly effective therapeutics were developed that may soon enable physicians to manage body weight in patients with obesity in a manner similar to the way that blood pressure is controlled in patients with hypertension. These medicines have grown out of a revolution in our understanding of the molecular and neural control of appetite and body weight, reviewed here.

Glucagon-like peptide 1 receptor agonists (GLP-1RAs) have changed considerably the management of type 2 diabetes (T2D). However, recently published data from retrospective cohort studies suggest that chronic exposure to GLP-1RAs in T2D may increase the risk of papillary and medullary thyroid cancer. In this perspective, the role of the incretin system in thyroid carcinogenesis has been reviewed and critically commented on, aiming to understand if the time has arrived to be concerned about the risk. Although evidence suggested, speculative hypotheses should be verified, and further studies are urgently needed to clarify the issue.

Diabetes is one of the chronic metabolic disorders which poses a multitude of life-debilitating challenges, including cardiac muscle impairment, which eventually results in heart failure. The incretin hormone glucagon-like peptide-1 (GLP-1) has gained distinct recognition in reinstating glucose homeostasis in diabetes, while it is now largely accepted that it has an array of biological effects in the body. Several lines of evidence have revealed that GLP-1 and its analogs possess cardioprotective effects by various mechanisms related to cardiac contractility, myocardial glucose uptake, cardiac oxidative stress and ischemia/reperfusion injury, and mitochondrial homeostasis. Upon binding to GLP-1 receptor (GLP-1R), GLP-1 and its analogs exert their effects via adenylyl cyclase-mediated cAMP elevation and subsequent activation of cAMP-dependent protein kinase(s) which stimulates the insulin release in conjunction with enhanced Ca²⁺ and ATP levels. Recent findings have suggested additional downstream molecular pathways stirred by long-term exposure of GLP-1 analogs, which pave the way for the development of potential therapeutic molecules with longer lasting beneficial effects against diabetic cardiomyopathies. This review provides a comprehensive overview of the recent advances in the understanding of the GLP-1R-dependent and -independent actions of GLP-1 and its analogs in the protection against cardiomyopathies.

The global prevalence of obesity is increasing rapidly with an exponential rise in incidence of type 2 diabetes mellitus in recent years. 'Diabesity', the term coined to show the strong interlink between obesity and diabetes, is the direct cons-equence of the obesity pandemic, and poses significant challenges in the management of the disease. Without addressing the clinical and mechanistic complications of obesity such as metabolic-associated fatty liver disease and obstructive sleep apnoea, a rational management algorithm for diabesity cannot be developed. Several classes of anti-diabetic medications including insulins, sulphonylureas, thiazolidinediones and meglitinides are associated with the risk of weight gain and may potentially worsen diabesity. Therefore, appropriate selection of antidiabetic drug regimen is crucial in the medical management of diabesity. The role of non-pharmacological measures such as dietary adjustments, exercise interventions and bariatric procedures should also be emphasised. Unfortunately, the importance of appropriate and optimal management of diabesity is often overlooked by medical professionals when achieving adequate glycemic control which results in inappropriate management of the disease and its complications. This review provides a narrative clinical update on the evidence behind the management of diabesity.

Obesity is a global pandemic that has been associated with the development of breast, endometrial, large intestine, renal, esophageal, and pancreatic cancer. Obesity is also involved in the development of cardiovascular disease and type 2 diabetes mellitus. Recently, an increase in the incidence of obesity-related cancers has been reported. Multiple myeloma (MM) is the second most common hematological malignancy, after lymphoma. The aim of this review is to examine the epidemiological data on obesity and MM, assess the effect of obesity on MM outcomes, evaluate the possible mechanisms through which obesity might increase the incidence of MM and provide the effects of obesity management on MM. Current evidence indicates that obesity may have an impact on the progression of monoclonal gammopathy of undetermined significance (MGUS) to MM and increase the prevalence of MM. However, data regarding the effect of obesity on MGUS incidence are controversial; further studies are needed to examine whether obesity affects the development of MGUS or the progression of MGUS to MM. In addition, obesity affects MM outcomes. Increased BMI is associated with decreased survival in patients with MM, while data regarding the effect of obesity on newly diagnosed MM subjects and autologous stem cell transplantation are limited. Interestingly, the obesity paradox may also apply to patients with relapsed/refractory MM who are overweight or obese, because they may have a survival advantage. The pathophysiological pathways linking obesity to MM are very complicated and include bone marrow adipose tissue; adipokines, such as adiponectin, leptin, resistin, and visfatin; inflammatory cytokines and growth factors, such as TNF-α and IL-6; hormones including insulin and the insulin-like growth factor system as well as sex hormones. In terms of the effect of pharmacological management of obesity, orlistat has been shown to alter the proliferation of MM cells, whereas no data exist on glucagon-like peptide-1 receptor agonists, naltrexone/bupropion, or phentermine/topiramate. Bariatric surgery may be associated with a reduction in the incidence of MM, however, further studies are needed.

Glucagon-like peptide-1 (GLP-1) is a 30-amino acid hormone secreted by L cells in the distal ileum, colon, and pancreatic α cells, which participates in blood sugar regulation by promoting insulin release, reducing glucagon levels, delaying gastric emptying, increasing satiety, and reducing appetite. GLP-1 specifically binds to the glucagon-like peptide-1 receptor (GLP-1R) in the body, directly stimulating the secretion of insulin by pancreatic β-cells, promoting proliferation and differentiation, and inhibiting cell apoptosis, thereby exerting a glycemic lowering effect. The glycemic regulating effect of GLP-1 and its analogues has been well studied in human and murine models in the circumstance of many diseases. Recent studies found that GLP-1 is able to modulate innate immune response in a number of inflammatory diseases. In the present review, we summarize the research progression of GLP-1 and its analogues in immunomodulation and related signal pathways.

It is a well-accepted fact that obesity and diabetes increase the risk of incidence of different cancers and their progression, leading to a decrease in the quality of life among affected cancer patients. In addition to decreasing the risk of cancers, maintaining a healthy body mass index (BMI)/body weight and/or blood glucose levels within the normal range critically impacts the response to anti-cancer therapy among affected individuals. A cancer patient managing their body weight and maintaining blood glucose control responds better to anti-cancer therapy than obese individuals and those whose blood glucose levels remain higher than normal during therapeutic intervention. In some cases, anti-diabetic/glucose-lowering drugs, some of which are also used to promote weight loss, were found to possess anti-cancer potential themselves and/or support anti-cancer therapy when used to treat such patients. On the other hand, certain glucose-lowering drugs promoted the cancer phenotype and risked cancer progression when used for treatment. Tirzepatide (TRZD), the glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide/gastric inhibitory peptide (GIP) agonist, has recently gained interest as a promising injectable drug for the treatment of type 2 diabetes and was approved by the FDA after successful clinical trials (SURPASS 1/2/3/4 and 5, NCT03954834, NCT03987919, NCT03882970, NCT03730662, and NCT04039503). In addition, the reports from the SURMOUNT-1 clinical trial (NCT04184622) support the use of TRZD as an anti-obesity drug. In the current review article, we examine the possibility and molecular mechanisms of how TRZD intervention could benefit cancer therapeutics or increase the risk of cancer progression when used as an anti-diabetic drug in diabetic patients.

Parkinson's disease (PD) is a chronic motor disorder, characterized by progressive loss of dopaminergic neurons. Numerous studies suggest that glucagon-like peptide-1 (GLP-1) secretagogue has a neuroprotective role in PD models. The present study evaluated potential of coffee bioactive compounds in terms of their ability to bind GPR-40/43 and tested the neuroprotective effect of best candidate on rotenone-induced PD mice acting via GLP-1 release. In silico molecular docking followed by binding free energy calculation revealed that chlorogenic acid (CGA) has a strong binding affinity for GPR-40/43 in comparison to other bioactive polyphenols. Molecular dynamics simulation studies revealed stable nature of GPR40-CGA and GPR43-CGA interaction and also provided information about the amino acid residues involved in binding. Subsequently, in vitro studies demonstrated that CGA-induced secretion of GLP-1 via enhancing cAMP levels in GLUTag cells. Furthermore, in vivo experiments utilizing rotenone-induced mouse model of PD revealed a significant rise in plasma GLP-1 after CGA administration (50 mg/kg, orally for 13 weeks) with concomitant increase in colonic GPR-40 and GPR-43 mRNA expression. CGA treatment also prevented rotenone-induced motor and cognitive impairments and significantly restored the rotenone-induced oxidative stress. Meanwhile, western blot results confirmed that CGA treatment downregulated rotenone-induced phosphorylated alpha-synuclein levels by upregulating PI3K/AKT signaling and inactivating GSK-3β through the release of GLP-1. CGA treatment ameliorated rotenone-induced dopaminergic nerve degeneration and alpha-synuclein accumulation in substantia nigra and augmented mean density of dopaminergic nerve fibers in striatum. These findings demonstrated novel biological function of CGA as a GLP-1 secretagogue. An increase in endogenous GLP-1 may render neuroprotection against a rotenone mouse model of PD and has the potential to be used as a neuroprotective agent in management of PD.

Obesity is a global health challenge. It is a multifactorial, complex, and progressive disease associated with various health complications and increased mortality. Lifestyle modifications are central to weight management but may be insufficient to maintain clinically meaningful weight loss. Pharmacotherapies are recommended as an adjunct to lifestyle interventions to induce and sustain clinically meaningful weight loss and reduce the risk of comorbidities in appropriate patients. Glucagon-like peptide-1 is an incretin metabolic hormone responsible for a range of physiological effects, including glucose and appetite regulation. Several glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been approved for the treatment of type 2 diabetes since 2005 including exenatide (short- and extended-release), lixisenatide, liraglutide, dulaglutide, albiglutide, and semaglutide. Of these, semaglutide (subcutaneous) and liraglutide are currently US Food and Drug Administration (FDA)-approved for chronic weight management in patients with or without diabetes. The phase 3 Semaglutide Treatment Effect in People with obesity (STEP) program was designed to investigate the effect of semaglutide versus placebo on weight loss, safety, and tolerability in adults with overweight or obesity. Following the submission of the results of the STEP 1-4 trials, the FDA approved once-weekly subcutaneous semaglutide 2.4 mg for chronic weight management in people with overweight or obesity in April 2021. Data from the program demonstrated that semaglutide (2.4 mg once weekly) achieved significant and sustained weight loss, together with improvements in cardiometabolic risk factors compared with placebo, and was generally well tolerated, with a safety profile consistent with other GLP-1RAs. The most common adverse events reported in STEP 1-5 were gastrointestinal events, which were transient, mild-to-moderate in severity, and typically resolved without permanent treatment discontinuation. This article reviews the data from STEP 1-5 and highlights clinically relevant findings for primary care providers.

Obesity is the most significant risk factor for the development of diabetes. Both obesity and diabetes rates have continued to increase in tandem and pose increased mortality for patients and increased health care costs for the community. Weight loss of 5% or more of total body weight renders improvements in glycemic control, decreases in the need for diabetes medications, and improved quality of life. Cotreatment of obesity and diabetes requires a comprehensive medical approach that encompasses intensive lifestyle modification including behavioral changes, nutrition, and physical activity, as well as pharmacotherapy and possible surgical management.

Type 2 diabetes (T2D), which has currently become a global pandemic, is a metabolic disease largely characterised by impaired insulin secretion and action. Significant progress has been made in understanding T2D aetiology and pathogenesis, which is discussed in this review. Extrapancreatic pathology is also summarised, which demonstrates the highly multifactorial nature of T2D. Glucagon-like peptide (GLP)-1 is an incretin hormone responsible for augmenting insulin secretion from pancreatic beta-cells during the postprandial period. Given that native GLP-1 has a very short half-life, GLP-1 mimetics with a much longer half-life have been developed, which are currently an effective treatment option for T2D by enhancing insulin secretion in patients. Interestingly, there is continual emerging evidence that these therapies alleviate some of the post-diagnosis complications of T2D. Additionally, these therapies have been shown to induce weight loss in patients, suggesting they could be an alternative to bariatric surgery, a procedure associated with numerous complications. Current GLP-1-based therapies all act as orthosteric agonists for the GLP-1 receptor (GLP-1R). Interestingly, it has emerged that GLP-1R also has allosteric binding sites and agonists have been developed for these sites to test their therapeutic potential. Recent studies have also demonstrated the potential of bi- and tri-agonists, which target multiple hormonal receptors including GLP-1R, to more effectively treat T2D. Improved understanding of T2D aetiology/pathogenesis, coupled with the further elucidation of both GLP-1 activity/targets and GLP-1R mechanisms of activation via different agonists, will likely provide better insight into the therapeutic potential of GLP-1-based therapies to treat T2D.

Given the relationship between the pathogenesis of obesity and type 2 diabetes mellitus (T2DM) as well as their significant health consequences, treatment strategies that can induce weight loss while achieving glycemic control are needed. Novel weight-reducing anti-diabetic agents along with anti-obesity medications (AOMs) can help medical providers address both conditions simultaneously and effectively.

This review summarizes and compares weight loss efficacy and glycemic control of weight-reducing anti-diabetic medications, AOMs and emerging pharmacologic agents that help treat both obesity and T2DM.

Management of obesity and T2DM can be challenging to achieve and sustain in the presence of obesogenic anti-diabetic agents. Utilizing weight-reducing anti-diabetic agents, AOMs, and endobariatric or surgical procedures, either separately or in combination, can help achieve better clinical outcomes in patients with obesity and T2DM. Some agents in development, such as tirzepatide and bimagrumab, are promising pharmacotherapy options that may change the standards of care for cardiometabolic disease management.

Insulin plays a significant role in carbohydrate homeostasis as the blood glucose lowering hormone. Glucose-induced insulin secretion (GSIS) is augmented by glucagon-like peptide (GLP-1), a gastrointestinal peptide released in response to ingesting nutriments. The secretion of insulin and GLP-1 is mediated by the binding of nutrients to G protein-coupled receptors (GPCRs) expressed by pancreatic β-cells and enteroendocrine cells, respectively. Therefore, insulin secretagogues and incretin mimetics currently serve as antidiabetic treatments. This study demonstrates the potency of synthetic isoprenoid derivatives of lysophosphatidylcholines (LPCs) to stimulate GSIS and GLP-1 release. Murine insulinoma cell line (MIN6) and enteroendocrinal L cells (GLUTag) were incubated with LPCs bearing geranic acid (1-GA-LPC), citronellic acid (1-CA-LPC), 3,7-dimethyl-3-vinyloct-6-enoic acid (GERA-LPC), and (E)-3,7,11-trimethyl- 3-vinyldodeca-6,10-dienoic acid (1-FARA-LPC). Respective free terpene acids were also tested for comparison. Besides their insulin- and GLP-1-secreting capabilities, we also investigated the cytotoxicity of tested compounds, the ability to intracellular calcium ion mobilization, and targeted GPCRs involved in maintaining lipid and carbohydrate homeostasis. We observed the high cytotoxicity of 1-GERA-LPC and 1-FARA-LPC in contrast 1-CA-LPC and 1-GA-LPC. Moreover, 1-CA-LPC and 1-GA-LPC demonstrated the stimulatory effect on GSIS and 1-CA-LPC augmented GLP-1 secretion. Insulin and GLP-1 release appeared to be GPR40-, GPR55-, GPR119- and GPR120-dependent.

GLP-1 receptor agonists (GLP-1 RAs) with exenatide b.i.d. first approved to treat type 2 diabetes in 2005 have been further developed to yield effective compounds/preparations that have overcome the original problem of rapid elimination (short half-life), initially necessitating short intervals between injections (twice daily for exenatide b.i.d.).

To summarize current knowledge about GLP-1 receptor agonist.

At present, GLP-1 RAs are injected twice daily (exenatide b.i.d.), once daily (lixisenatide and liraglutide), or once weekly (exenatide once weekly, dulaglutide, albiglutide, and semaglutide). A daily oral preparation of semaglutide, which has demonstrated clinical effectiveness close to the once-weekly subcutaneous preparation, was recently approved. All GLP-1 RAs share common mechanisms of action: augmentation of hyperglycemia-induced insulin secretion, suppression of glucagon secretion at hyper- or euglycemia, deceleration of gastric emptying preventing large post-meal glycemic increments, and a reduction in calorie intake and body weight. Short-acting agents (exenatide b.i.d., lixisenatide) have reduced effectiveness on overnight and fasting plasma glucose, but maintain their effect on gastric emptying during long-term treatment. Long-acting GLP-1 RAs (liraglutide, once-weekly exenatide, dulaglutide, albiglutide, and semaglutide) have more profound effects on overnight and fasting plasma glucose and HbA1c, both on a background of oral glucose-lowering agents and in combination with basal insulin. Effects on gastric emptying decrease over time (tachyphylaxis). Given a similar, if not superior, effectiveness for HbA1c reduction with additional weight reduction and no intrinsic risk of hypoglycemic episodes, GLP-1RAs are recommended as the preferred first injectable glucose-lowering therapy for type 2 diabetes, even before insulin treatment. However, GLP-1 RAs can be combined with (basal) insulin in either free- or fixed-dose preparations. More recently developed agents, in particular semaglutide, are characterized by greater efficacy with respect to lowering plasma glucose as well as body weight. Since 2016, several cardiovascular (CV) outcome studies have shown that GLP-1 RAs can effectively prevent CV events such as acute myocardial infarction or stroke and associated mortality. Therefore, guidelines particularly recommend treatment with GLP-1 RAs in patients with pre-existing atherosclerotic vascular disease (for example, previous CV events). The evidence of similar effects in lower-risk subjects is not quite as strong. Since sodium/glucose cotransporter-2 (SGLT-2) inhibitor treatment reduces CV events as well (with the effect mainly driven by a reduction in heart failure complications), the individual risk of ischemic or heart failure complications should guide the choice of treatment. GLP-1 RAs may also help prevent renal complications of type 2 diabetes. Other active research areas in the field of GLP-1 RAs are the definition of subgroups within the type 2 diabetes population who particularly benefit from treatment with GLP-1 RAs. These include pharmacogenomic approaches and the characterization of non-responders. Novel indications for GLP-1 RAs outside type 2 diabetes, such as type 1 diabetes, neurodegenerative diseases, and psoriasis, are being explored. Thus, within 15 years of their initial introduction, GLP-1 RAs have become a well-established class of glucose-lowering agents that has the potential for further development and growing impact for treating type 2 diabetes and potentially other diseases.

New-onset diabetes mellitus after transplantation (NODAT) is a frequent complication in kidney allograft recipients. It may be caused by modifiable and non-modifiable factors. The non-modifiable factors are the same that may lead to the development of type 2 diabetes in the general population, whilst the modifiable factors include peri-operative stress, hepatitis C or cytomegalovirus infection, vitamin D deficiency, hypomagnesemia, and immunosuppressive medications such as glucocorticoids, calcineurin inhibitors (tacrolimus more than cyclosporine), and mTOR inhibitors. The most worrying complication of NODAT are major adverse cardiovascular events which represent a leading cause of morbidity and mortality in transplanted patients. However, NODAT may also result in progressive diabetic kidney disease and is frequently associated with microvascular complications, eventually determining blindness or amputation. Preventive measures for NODAT include a careful assessment of glucose tolerance before transplantation, loss of over-weight, lifestyle modification, reduced caloric intake, and physical exercise. Concomitant measures include aggressive control of systemic blood pressure and lipids levels to reduce the risk of cardiovascular events. Hypomagnesemia and low levels of vitamin D should be corrected. Immunosuppressive strategies limiting the use of diabetogenic drugs are encouraged. Many hypoglycemic drugs are available and may be used in combination with metformin in difficult cases. In patients requiring insulin treatment, the dose and type of insulin should be decided on an individual basis as insulin requirements depend on the patient's diet, amount of exercise, and renal function.

In September 2019, the U.S. Food and Drug Administration approved oral semaglutide as the first orally administered glucagon-like peptide 1 (GLP-1) receptor agonist for treating people with type 2 diabetes. Although injectable GLP-1 receptor agonists are well-established treatment options for people with type 2 diabetes, clinical experience with an oral formulation in this class is limited. This article provides practical guidance for diabetes care and education specialists on how to effectively counsel patients initiating therapy with oral semaglutide on appropriate administration of the treatment and its possible effects on glycemic control, body weight, and quality of life. Strategies for mitigating potential side effects typical of the GLP-1 receptor agonist class, namely nausea, vomiting, and diarrhea, are also provided. Involving patients in treatment decisions and educating them about available and prescribed medications are key strategies for encouraging treatment adherence and ensuring optimal therapeutic outcomes.

Quantify association between the glucagon-like peptide-1 receptor agonist liraglutide and risk of thyroid cancer (TC) compared to other antidiabetics.

Initiators of liraglutide, exenatide, metformin, pioglitazone or groups of dipeptidyl peptidase-4 inhibitors or sulfonylureas were identified in a US health plan (2010-2014) and followed for a median of 17 months. Thyroid cancer cases during follow-up were identified via a validated algorithm. Incidence rates of TC among liraglutide and comparators were assessed using relative risks estimated within propensity score-matched cohorts using intention to treat (ITT) and time on drug analyses. Latency effects and potential surveillance bias were evaluated.

Relative risks from ITT analyses ranged from 1.00 (95% confidence interval (CI) 0.56-1.79) versus metformin to 1.70 (95% CI 1.03-2.81) versus all comparators excluding exenatide. Effect estimates from latency analyses were slightly attenuated. Time on drug analyses suggested no increased risk for either longer duration or higher cumulative dose of liraglutide. Medical record review found 85% were papillary or a follicular variant of papillary or both; 46% were microcarcinomas (≤10 millimeters), which were more prevalent in the liraglutide cohort (67% versus 43% in all comparators).

Relative risks were elevated for several comparisons, which should be interpreted cautiously because of potential residual confounding and surveillance bias. Liraglutide cases had smaller thyroid nodules and shorter time-to-diagnosis, suggesting increased surveillance for TC among liraglutide initiators, especially shortly after the drug´s approval. After adjusting the primary analyses (ITT) for latency, no significant elevated risk of TC was observed among liraglutide initiators.

Activation of neuropeptide Y2 receptors (NPYR2) by the N-terminally truncated, dipeptidyl peptidase-4 (DPP-4) generated, Peptide YY (PYY) metabolite, namely PYY(3-36), results in satiating actions. However, PYY(3-36) is also subject to C-terminal enzymatic cleavage, which annuls anorectic effects.

Substitution of l-Arg³⁵ with d-Arg³⁵ in the DPP-4 stable sea lamprey PYY(1-36) peptide imparts full C-terminal stability. In the current study, we have taken this molecule and introduced DPP-4 susceptibility by Iso³ substitution.

As expected, [Iso³]sea lamprey PYY(1-36) and [Iso³](d-Arg³⁵)sea lamprey PYY(1-36) were N-terminally degraded to respective PYY(3-36) metabolites in plasma. Only [Iso³](d-Arg³⁵)sea lamprey PYY(1-36) was C-terminally stable. Both peptides possessed similar insulinostatic and anti-apoptotic biological actions to native PYY(1-36) in beta-cells. Unlike native PYY(1-36) and [Iso³](d-Arg³⁵)sea lamprey PYY(1-36), [Iso³]sea lamprey PYY(1-36) displayed some proliferative actions in Npyr1 knockout beta-cells. In addition, [Iso³]sea lamprey PYY(1-36) induced more rapid NPYR2-dependent appetite suppressive effects in mice than its C-terminally stable counterpart. Twice daily administration of either peptide to high fat fed (HFF) mice resulted in significant body weight reduction and improvements in circulating triglyceride levels. [Iso³]sea lamprey PYY(1-36) treatment also prevented elevations in glucagon. Both peptides, and especially [Iso³]sea lamprey PYY(1-36), improved glucose tolerance. The treatment interventions also partially reversed the deleterious effects of sustained high fat feeding on pancreatic islet morphology.

The present study confirms that sustained NPYR2 receptor activation by [Iso³](d-Arg³⁵)sea lamprey induced significant weight lowering actions. However, identifiable benefits of this peptide over [Iso³]sea lamprey PYY(1-36), which was not protected against C-terminal degradation, were not pronounced.

The use of glucagon-like peptide-1 (GLP-1) analogues has been linked to the risk of thyroid cancer. Spontaneous reports can provide information about rare adverse events occurring after the time of marketing. Our objective was to detect, from the European pharmacovigilance database (EudraVigilance), a signal of thyroid cancer during GLP-1 analogues treatment in patients with diabetes.

Herein, we analysed all reports of thyroid cancer reported with GLP-1 analogues in EudraVigilance database from their first marketing authorization till 30 January 2020. A case/non-case method was used to assess the association between thyroid cancer and GLP-1 analogues, calculating proportional reporting ratios (PRRs) and their 95% confidence interval (CI) as a measure of disproportionality. The cases were identified with Medical Dictionary for Regulatory Activities (MedDRA) version 22.1.

There were 11 243 cases of thyroid cancer and related preferred terms (PTs) in the 6 665 794 reports recorded in EudraVigilance during the study period. GLP-1 analogues were involved in 236 cases. Exenatide, liraglutide and dulaglutide met the criteria to generate a safety signal, suggesting that thyroid cancer is reported relatively more frequently in association with these drugs than with other medicinal products. The association was strongest for liraglutide followed by exenatide with PRR of 27.5 (95% CI, 22.7-33.3) and 22.5 (95% CI, 17.9-28.3), respectively. Disproportionality was also observed for GLP-1 analogues and individual identified preferred term, that is thyroid cancer (N = 111), medullary thyroid cancer (N = 64) and thyroid neoplasm (N = 46) with PRR of 14.4 (95% CI, 11.8-17.4), 221.5 (95% CI, 155.7-315.1) and 35.5 (95% CI, 25.9-48.5), respectively.

Our findings showed disproportionality for thyroid cancer, medullary thyroid cancer and thyroid neoplasm in patients treated with GLP-1 analogues. We have found evidence from spontaneous reports that GLP-1 analogues are associated with thyroid cancer in patients with diabetes.

This retrospective study investigated the association between worrisome pathological features of papillary thyroid cancer indicative of invasion and type 2 diabetes, as well as antihyperglycemic drug therapy for diabetes.

The records of 14,167 patients who had undergone primary surgery for thyroid cancer were retrospectively reviewed and screened for concomitant diabetes. The diabetic and nondiabetic groups were age and gender matched, and further stratified by treatment, including five single antihyperglycemic drugs.

The study population comprised 942 patients, including 471 patients each with and without diabetes. The rate of worrisome pathological features was higher in diabetic patients than in nondiabetic patients (49.26% cf. 30.57%, P < 0.001), mainly reflected by extrathyroidal extension (34.82% cf. 5.94%, P < 0.001) and lymph node metastasis (42.68% cf. 33.55%, P < 0.001). The number of lymph node metastases in those treated with acarbose (0.32) was significantly lower compared with groups given any of the other four antihyperglycemic drugs (ranging from 1.51 to 2.15; P = 0.001 to 0.05).

Papillary thyroid cancer complicated with type 2 diabetes has a higher risk of invasive tumor growth. Compared with other antihyperglycemic drugs, patients with acarbose had the lowest risk of aggressive tumor growth. These results may evoke pathophysiological hypotheses to be explored in preclinical and clinical studies.

Given that adverse remodeling is the leading cause of heart failure and death in the USA, there is an urgent unmet need to develop new methods in dealing with this devastating disease. Here we evaluated the efficacy of a short-course glucagon-like peptide-1 receptor agonist therapy-specifically 2-quinoxalinamine, 6,7-dichloro-N-(1,1-dimethylethyl)-3-(methylsulfonyl)-,6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline (DMB; aka Compound 2) - in attenuating adverse LV remodeling. We also examined the role, if any, of mitochondrial turnover in this process. Wild-type, Parkin knockout and MitoTimer-expressing mice were subjected to permanent coronary artery ligation, then treated briefly with DMB. LV remodeling and cardiac function were assessed by histology and echocardiography. Autophagy and mitophagy markers were examined by western blot and mitochondrial biogenesis was inferred from MitoTimer protein fluorescence and qPCR. We found that DMB given post-infarction significantly reduced adverse LV remodeling and the decline of cardiac function. This paralleled an increase in autophagy, mitophagy and mitochondrial biogenesis. The salutary effects of the drug were lost in Parkin knockout mice, implicating Parkin-mediated mitophagy as part of its mechanism of action. Our findings suggest that enhancing Parkin-associated mitophagy and mitochondrial biogenesis after infarction is a viable target for therapeutic mitigation of adverse remodeling.

Chronic kidney disease (CKD) in patients with diabetes mellitus (DM) is a major problem of public health. Currently, many of these patients experience progression of cardiovascular and renal disease, even when receiving optimal treatment. In previous years, several new drug classes for the treatment of type 2 DM have emerged, including inhibitors of renal sodium-glucose co-transporter-2 (SGLT-2) and glucagon-like peptide-1 (GLP-1) receptor agonists. Apart from reducing glycaemia, these classes were reported to have other beneficial effects for the cardiovascular and renal systems, such as weight loss and blood pressure reduction. Most importantly, in contrast to all previous studies with anti-diabetic agents, a series of recent randomized, placebo-controlled outcome trials showed that SGLT-2 inhibitors and GLP-1 receptor agonists are able to reduce cardiovascular events and all-cause mortality, as well as progression of renal disease, in patients with type 2 DM. This document presents in detail the available evidence on the cardioprotective and nephroprotective effects of SGLT-2 inhibitors and GLP-1 analogues, analyses the potential mechanisms involved in these actions and discusses their place in the treatment of patients with CKD and DM.

Today, excluding insulin, there are eight classes of anti-diabetic medicines that have been added to the pharmacy since the introduction of metformin in the mid-1950s; the sulfonylureas, biguanides, thiazolidinediones, α-glucosidase inhibitors, meglitinides, incretins, and sodium glucose transport 2 inhibitors. Does the fact that metformin is still first-line treatment suggest that our drug discovery efforts over the past 60 years have not been good enough? Or does it suggest that diabetes is such a complex disorder that no single treatment, other than gastric bypass surgery, can affect true normalization of not only blood sugar but also the underlying pathologies? Our understanding of the disease has most definitely improved which may bring hope for the future in terms of science, but for it to be beneficial, this science has to be translated into better drug treatments for the disease. In this review, I have examined the eight classes of anti-diabetes drugs from a drug discovery perspective.

The rising epidemic of type 2 diabetes mellitus & associated complications is a serious cause of concern for humanity. Glucagon-like peptide-1 receptor agonists commonly abbreviated as GLP-1 RAs, emerged as a promising therapeutic class based on incretin therapy that regulates glucose metabolism through multiple mechanisms. In the present study, various investigational & clinically used GLP-1 RAs have been reviewed with emphasis on their efficacy, structural modifications, adverse effects and toxicities. Various clinical trials justifying their efficacy have also been included, which highlighted the potential of GLP-1 RAs over conventional anti hyperglycaemic agents through a study of pooled effect on glycemic efficacy and weight-loss. The significant potency and appreciable safety of GLP-1 RAs manifested their potential as a logical approach for the management of type 2 diabetes.

Diabetes mellitus (DM) and thyroid dysfunction (TD) often tend to coexist in patients. Both hypothyroidism and hyperthyroidism are more common in type 2 diabetes mellitus (T2DM) patients than in their nondiabetic counterparts. Current guidelines are neither clear nor specific about the frequency of thyroid function monitoring in T2DM patients. Circulating thyroid hormones affect several different organs and cells, have a major impact on glucose, lipid, and protein metabolism, and can worsen glycaemic control in T2DM. Hyperthyroidism and thyrotoxicosis can worsen subclinical DM and cause hyperglycaemia in T2DM patients, increasing the risk of diabetic complications. T2DM reduces thyroid-stimulating hormone levels and impairs the conversion of thyroxine (T4) to triiodothyronine (T3) in the peripheral tissues. Poorly managed T2DM can lead to insulin resistance and hyperinsulinaemia, which causes thyroid tissue proliferation and increases nodule formation and goitre size. In addition, while metformin can be beneficial in both T2DM and TD patients, other antidiabetics such as sulfonylureas, pioglitazone, and thiazolidinediones can negatively impact TD. Antithyroid drugs such as methimazole can impair glycaemic control in T2DM patients. Thyrovigilance in T2DM patients and diabetovigilance in TD patients may therefore be necessary to facilitate individualized care and management.Funding: Abbott India Ltd.

Overweight and obesity constitute a global pandemic with devastating consequences that affect >2 billion people. Obesity plays a central role in morbidity and mortality of diseases of multiple organs and systems, and it is a major contributor to the growing incidence of cancer. There is now sufficient level of evidence for the association between overweight and 11 types of cancer, among which are two of the most common cancers worldwide, those of the colorectum and postmenopausal breast. Sedentary lifestyle, unhealthy diet, and excessive alcohol intake also account for the burden of cancer by promoting obesity. The risk of specific types of cancer is also directly influenced, regardless of the magnitude of adiposity, by physical inactivity, consumption of red meat, processed meat and ultra-processed foods, dairy products, alcohol, whole grain cereals, nuts, vegetables, and fruits. Type 2 diabetes is another global health threat closely associated with obesity that boosts the risk of cancer driven by high BMI. Education to promote positive choices and physical activity and resolute public health interventions on food delivery are requested to reduce the burden of obesity-related cancer and lighten the unsustainable growing expenses to health systems.

iGlarLixi is a titratable, fixed-ratio combination of insulin glargine (100 units/mL) and lixisenatide (33 μg/mL). This review evaluates the overall safety and adverse event (AE) profile of iGlarLixi in patients with type 2 diabetes.

We collated patient-level data from the phase 2 LixiLan proof-of-concept trial and the phase 3 LixiLan-L (insulin-experienced patients) and LixiLan-O (insulin-naïve patients) trials to evaluate AEs associated with iGlarLixi. We also describe data from the ELIXA study to examine pancreatitis and pancreatic cancer, and the ELIXA and ORIGIN studies for cardiovascular safety data.

Patients treated with iGlarLixi had improved glycemic control with a similar incidence of documented symptomatic hypoglycemia (plasma glucose ≤ 70 mg/dL) compared with iGlar. Incidence of severe hypoglycemia (an event requiring third-party assistance) was low in all treatment arms in both LixiLan-L and LixiLan-O. Rates of gastrointestinal AEs in patients treated with iGlarLixi tended to be lower compared with lixisenatide alone, but higher than those treated with iGlar alone. Gastrointestinal AEs were generally mild to moderate in intensity and transient. Antibodies formed in response to iGlarLixi did not have any significant clinical impact, with similar safety observed for antibody-positive and antibody-negative populations. Rates of allergic reactions, malignancy, renal impairment, and cardiovascular events were low and comparable between treatment groups. Older age (≥ 65 years) and gender did not affect efficacy or safety.

iGlarLixi has a safety profile that is consistent with that of its two active components insulin glargine and lixisenatide, with no signals for pancreatitis or thyroid C cell tumors, and no black-box warning for iGlarLixi. There were no unexpected safety findings; iGlarLixi had beneficial effects on glycemic control, with no increased risk of hypoglycemia, despite a greater glycated hemoglobin A1c reduction. In addition, there were also fewer gastrointestinal AEs associated with iGlarLixi compared with lixisenatide alone.

Sanofi US Inc.

Semaglutide once-weekly glucagon-like peptide-1 receptor agonist (GLP-1 RA) injection has been approved as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes mellitus (T2DM). Areas Covered: The safety and efficacy of the semaglutide once-weekly injection are reviewed using results from preliminary pharmacology studies and later-phase randomized control trials (RCTs) and meta-analyses. Semaglutide once-weekly is compared to placebo and active comparators for T2DM in the SUSTAIN clinical trial series, with outcomes of: glycemic control, weight loss, major adverse cardiovascular events, and adverse effects. Risk for diabetic retinopathy complications (DRCs) is reviewed in detail, due to significantly higher risk for DRCs seen in SUSTAIN 6. SUSTAIN 6 is the first instance of a GLP-1 RA demonstrating significantly increased risk for DRCs. Semaglutide's current regulatory approvals, practice considerations, and cost-effectiveness compared to similar therapies are also considered. Expert Commentary: Semaglutide demonstrates high glycemic efficacy and favorable safety profile, and reduces the risk for cardiovascular events. Mild to moderate gastrointestinal events and retinopathy complications were more common with semaglutide compared to placebo, though serious adverse events were similar to controls and infrequent. Improved clinical efficacy should be carefully weighed against the risk for GI and retinopathy complications.

Type 2 diabetes mellitus (T2D) is a major risk factor for cardiovascular disease (CVD), the most common cause of death in T2D. Despite improved risk factor control, however, adults with T2D continue to experience substantial excess CVD risk. Until recently, however, improved glycemic control has not been associated with robust macrovascular benefit. The advent of 2 new classes of antihyperglycemic agents, the sodium-glucose cotransporter-2 inhibitors and the glucagon-like peptide-1 receptor agonists, and their respective large cardiovascular outcome trials, has led to a paradigm shift in how cardiologists and heath care practitioners conceptualize T2D treatment. Herein, the authors review the recent trial evidence, the potential mechanisms of action of the sodium-glucose cotransporter-2 inhibitors and the glucagon-like peptide-1 receptor agonists, safety concerns, and their use for the primary prevention of CVD as well as in diabetic patients with impaired renal function and heart failure.

The aim of the present study is to examine the effects on cognitive performance, anthropometric measures, and metabolic markers in 2 different treatments: Incretins vs sodium-glucose co-transporter-2 inhibitors (SGLT2-I).

A randomized controlled clinical trial was carried out on 39 elderly subjects (23 men and 16 women) with type 2 diabetes mellitus, with a mean age of 77.21±8.07 years. Body mass index (BMI) of 29.92±4.31 kg/m2 and a cognitive status measured by a Mini Mental State Examination (scores >27 points). The subjects were on a 3-month treatment with a maximal dose of metformin as a stable regime, with the addition of incretins (liraglutide at doses of up to 1.8 mg/d; vildagliptin at 100 mg/d; sitagliptin 100 mg/d; and linagliptin 5 mg/d), or SGLT2-I (canagliflozin 300 mg/d; empagliflozin 25 mg/d; and dapagliflozin 10 mg/d). Glucose control was monitored by fasting glucose and glycosylated hemoglobin. Cognitive performance (by way of Verbal Fluency Test, Attentive Matrices Test, and Babcock Story Recall Test), anthropometric measures, and plasma lipids were also evaluated.

Cognitive status did not change significantly during the 12 months of treatment in either group: Verbal Fluency Test: (SGLT2-I: P=1.00, incretins: P=0.598); Babcock Story Recall Test (SGLT2-I: P=0.391; incretins: P=0.351); and Attentive Matrices Test (SGLT2-I: P=0.679, incretins: P=0.901). SGLT2-I also resulted in a reduction in weight (-1.95 kg; P<0.05), in BMI (-0.69 kg/m2; P<0.05) and an increase in high-density lipoprotein cholesterol (+5.73 mg/dl; P<0.01).

Preliminary data show that patients treated with incretins and SGLT2-I have not suffered a reduction in cognitive performance during the 1 year of treatment. Metabolic outcome seemed to benefit, in particular, in patients who were treated with SGLT2-I.

Current management options for treating type 2 diabetes are diverse. Many different classes of antidiabetes therapies are used in clinic, and several new candidates are in late-phase clinical trial. This therapeutic abundance is a windfall for patients because it facilitates individualized patient care. Evidence-based positioning of these agents is challenging, however, requiring comprehensive and balanced familiarity with each drug class. In this review, I provide a clinical update of glucagon-like peptide-1 receptor agonists (GLP-1RAs), a class of incretin-based, injectable antidiabetes therapies which improve fasting and postprandial blood glucose control through glucose-dependent pancreatic islet cell hormone secretion without significant risks for hypoglycemia. Chronic use of GLP-1RAs also promotes body weight loss through stimulation of GLP-1 receptors localized in hypothalamic satiety centres that regulate appetite, resulting in reduced caloric intake. Since 2005, when GLP-1RAs first received regulatory approval for type 2 diabetes, this class has expanded to include long-acting, once-weekly GLP-1RAs. Recent cardiovascular outcome trials demonstrate that long-term use of GLP-1RAs (liraglutide and semaglutide) reduce cardiovascular and renal complications of diabetes. Illustrating that GLP-1RAs are favourable in high-risk patients with type 2 diabetes. This review provides a clinical appraisal of the GLP-1RA class, highlighting intraclass similarities and differences, summarizing the clinical development of incretin-based diabetes therapies and focusing on currently approved GLP-1RAs. The review also discusses the implications of structural differences between GLP-1RA molecules and comments on the risks and benefits associated with GLP-1RAs and their positioning in treating type 2 diabetes.