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A systematic review regarding the efficacy of newer antihyperglycemic agents (including PPAR agonists, GLP-1 receptor agonists and SGLT-2 inhibitors) for the treatment of NAFLD/NASH

GLP-1 (Glucagon like Peptide-1) receptor agonists have been shown to be effective in the treatment of type 2 diabetes mellitus (T2DM). Although the first GLP-1 receptor agonist, Exenatide, was approved in the year 2000, other agents with a longer duration of action that do not require twice-daily dosing are now being developed. Indeed, Liraglutide, a once-daily GLP-1 receptor agonist, was approved in 2010, a once-weekly extended-release formulation of Exenatide (Exenatide ER) was approved in 2011 and now more recently Semaglutide, an oral GLP 1 receptor agonist was approved for medical use in the United States in September 2019 and in the European Union in April 2020. The importance of GLP-1 itself and the use of GLP-1 receptor agonists in T2DM are discussed. An overview of the clinical development of the GLP-1 receptor agonists (Exenatide ER, Liraglutide, Lixisenatide, Albiglutide, Taspoglutide and Semaglutide) is provided and their mechanism of action, efficacy in terms of glycaemic control, weight loss and tolerability are reviewed. Keywords: GLP1 receptor agonist; Liraglutide; Exenatide ER; Lixisenatide; Semaglutide

Randomized controlled trials (RCTs) have consistently shown glycemic and extra-glycemic benefits of long-acting injectable glucagon-like-peptide-1 receptor agonists (GLP-1RAs, liraglutide, albiglutide, exenatide once-weekly, dulaglutide, and semaglutide) in terms of reduction in the rates of cardiovascular events and mortality among patients with type 2 diabetes. Recently, the analyses of large datasets collecting routinely-accumulated data from clinical practice (ie, real-world studies, RWS) have provided new opportunities to complement the information obtained from RCTs. In this narrative review, we addressed clinically relevant questions that might be answered by well-conducted RWS: are subjects treated with GLP-1RAs in the "real-world" similar to those included in RCTs? Is the performance of GLP-1RA observed in the RWS (effectiveness) similar to that described in RCTs (efficacy)? Is the effectiveness similar in population of patients generally under-represented in RCTs? Are the cardiovascular benefits of GLP-1RAs confirmed in RWS? We also describe a few comparisons currently un-explored by specific RCTs, such as direct comparison between different administration strategies (eg, fixed- versus flexible-combination with basal-insulin) or between GLP-1RAs versus dipeptidyl-peptidase-4 inhibitor (DDP4i) or versus sodium/glucose cotransporter-2 inhibitors (SGLT-2i) on hard cardio-renal outcomes. Altogether, RWS provide highly informative information on treatment with GLP-1RAs. On the one side, RWS showed different clinical characteristics between subjects enrolled in RCTs versus those attending real-world clinics and receiving a GLP-1RA. On the other hand, RWS showed that GLP-1RA effectiveness is overall consistent in subgroups of patients less represented in RCTs. In addition, RWS allowed the identification of modifiable factors (eg, titration or adherence) that might guide physicians towards better GLP-1RAs use. Finally, multiple RWS reported better cardio-renal outcomes with GLP-1RAs than with DPP-4i, while initial findings from RWS described a weaker cardiovascular protection compared to SGLT-2i. Therefore, there is the need for further RWS and RCTs comparing these different classes of glucose lowering medications.

Glucagon-like peptide-1 (GLP-1) receptor agonists are a class of incretin-based therapies for the management of hyperglycemia and, in some cases, cardiovascular risk in people with type 2 diabetes. These agents act on multiple physiological pathways involved in type 2 diabetes with the effect of increasing insulin secretion and decreasing glucagon to control glucose levels (1,2). They also transiently slow gastric emptying, reduce appetite, and facilitate weight loss and other metabolic improvements (3). Consensus recommendations from the American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) and American Association of Clinical Endocrinologists/American College of Endocrinology advocate that GLP-1 receptor agonists, among other therapies, should be considered as a second-line treatment option in people with type 2 diabetes when glucose levels are not well controlled on metformin (4–6). Additionally, in patients with type 2 diabetes and atherosclerotic cardiovascular disease or chronic kidney disease, a GLP-1 receptor agonist or sodium–glucose cotransporter 2 (SGLT2) inhibitor with proven cardiovascular benefit is recommended as a first-line therapy for the reduction of cardiovascular risk (4–6). GLP-1 receptor agonists may also be used as a first-line treatment in those who cannot use metformin or when reduced renal function precludes metformin use (human-based GLP-1 receptor agonists only) (4–6). In particular, the recommendations favor GLP-1 receptor agonists and SGLT2 inhibitors because they have a low risk of hypoglycemia and promote weight loss (5). Several GLP-1 receptor agonists are available in the United States and worldwide, some of which are analogs of human GLP-1 (dulaglutide, liraglutide, and semaglutide), whereas others are exendin-based (exenatide and lixisenatide) (7–13). The GLP-1 receptor agonist albiglutide was also approved, but has been withdrawn for commercial reasons. Until recently, all GLP-1 receptor agonists were administered by subcutaneous injection, although a once-daily oral formulation …

Over recent decades, an improved understanding of the pathophysiology of type 2 diabetes mellitus (T2DM) and glucose regulation has led to innovative research and new treatment paradigms. The discovery of the gut peptide glucagon-like peptide-1 (GLP-1) and its role in glucose regulation paved the way for the class of GLP-1 receptor agonist compounds, or GLP-1RAs. The long-acting GLP-1RAs (dulaglutide, exenatide extended-release, liraglutide, semaglutide [injectable and oral]) are classified as such based on a minimum 24-hour duration of clinically relevant effects after administration. In phase 3 clinical trial programs of long-acting GLP-1RAs, A1C typically was reduced in the range of 1% to 1.5%, with reductions close to 2% in some studies. GLP-1RAs when used alone (without sulfonylureas or insulin) have a low risk of hypoglycemia because, like endogenous GLP-1, their insulinotropic effects are glucose-dependent. In addition to local actions in the gastrointestinal (GI) tract, GLP-1RAs stimulate receptors in the central nervous system to increase satiety, resulting in weight loss. All long-acting GLP-1RAs have, at minimum, been shown to be safe and not increase cardiovascular (CV) risk and most (liraglutide, semaglutide injectable, dulaglutide, albiglutide) have been shown in CV outcomes trials (CVOTs) to significantly reduce the risk of major cardiac adverse events. The class has good tolerability overall, with generally transient GI adverse events being most common. The weekly injectable agents offer scheduling convenience and may promote treatment adherence. One long-acting GLP-1RA is available as an oral daily tablet, which may be preferable for some patients and providers.

Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are emerging as an important therapy to consider for patients with type 2 diabetes (T2D) given this class of treatment’s ability to reduce glycated haemoglobin and their associated weight loss and low risk for hypoglycaemia. Additionally, seven cardiovascular outcomes trials (CVOTs) have been performed in the past 4 years using lixisenatide, liraglutide, semaglutide, exenatide, albiglutide, dulaglutide and oral semaglutide. All have found non-inferiority for cardiovascular outcomes, with many finding superiority of these drugs. These findings have transformed our guidelines on pharmacological treatment of T2D. This review article will discuss GLP-1 RA therapy, review the seven CVOTs reported to date and discuss the implications on current guidelines and therapies going forward.

GLP-1, a peptide hormone secreted from the gut, stimulating insulin and suppressing glucagon secretion was identified as a parent compound for novel treatments of diabetes, but was degraded (dipeptidyl peptidase-4) and eliminated (mainly by kidneys) too fast (half-life 1–2 min) to be useful as a therapeutic agent. GLP-1 receptor agonist has been used to treat patients with type 2 diabetes since 2007, when exenatide (twice daily) was approved in 2007. Compounds with longer duration of action (once daily, once weekly) and with increasingly better efficacy with respect to glycaemic control and body weight reduction have been developed, and in a recent ADA/EASD consensus statement, were recommended as the first injectable diabetes therapy after failure of oral glucose-lowering medications. Most GLP-1 receptor agonists (lixisenatide q.d., liraglutide q.d., exenatide q.w., dulaglutide q.w., albiglutide q.w., semaglutide q.w., all for s.c. injection, and the first oral preparation, oral semaglutide) have been examined in cardiovascular outcomes studies. Beyond proving their safety in vulnerable patients, most of whom had pre-existing heart disease, liraglutide, semaglutide, albiglutide, and dulaglutide reduced the time to first major adverse cardiovascular events (non-fatal myocardial infarction and stroke, cardiovascular death). Liraglutide, in addition, reduced cardiovascular and all-cause mortality. It is the purpose of the present review to describe clinically important differences, regarding pharmacokinetic behaviour, glucose-lowering potency, effectiveness of reducing body weight and controlling other cardiovascular risk factors, and of the influence of GLP-1 receptor agonist treatment on cardiovascular outcomes in patients either presenting with or without pre-existing cardiovascular disease (atherosclerotic, ischemic or congestive heart failure).

Major cardiovascular (CV) outcome trials with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are currently available. These agonists have proven their CV safety, in harmony with the US Food and Drug Administration (FDA) recommendation for antidiabetic drugs. The potential cardioprotective effect of incretin-based therapies is attributed to their multiple non-glycaemic actions in the CV system, including changes in insulin resistance, weight loss, reduction in blood pressure, improved lipid profile and direct effects on the heart and vascular endothelium. Liraglutide, semaglutide and albiglutide have been demonstrated to reduce the risk of major adverse cardiac events (MACE), whereas lixisenatide and extended-release exenatide had a neutral effect. Thus, it is conceivable that there are different drug-specific properties across the class of GLP-1 RAs. In this review, we discuss the results of the five recently published randomised CV outcome trials with GLP-1 RAs, along with the potential differences and the pleiotropic actions of these agents on the CV system. Keywords: Cardiovascular disease, Diabetes mellitus, Randomised controlled trials, Treatment

OBJECTIVE Fixed-ratio combinations of basal insulin plus glucagon-like peptide 1 receptor agonist (GLP-1 RA) allow concomitant administration of two proven complementary injectable therapies for type 2 diabetes. This study investigated switching to a titratable fixed-ratio combination of insulin glargine plus lixisenatide (iGlarLixi) in patients with type 2 diabetes receiving daily or weekly GLP-1 RA therapy. RESEARCH DESIGN AND METHODS LixiLan-G, a randomized, open-label, 26-week trial, compared switching to iGlarLixi versus continuing prior GLP-1 RA in patients with type 2 diabetes and HbA1c 7–9% (53–75 mmol/mol) taking maximum tolerated doses of a GLP-1 RA daily (60% on liraglutide once daily or exenatide twice daily) or weekly (40% on dulaglutide, exenatide extended release, or albiglutide) with metformin with or without pioglitazone and with or without sodium–glucose cotransporter 2 inhibitors. Adherence to randomized treatment was closely monitored throughout the study. RESULTS iGlarLixi (n = 257) reduced HbA1c more than continued GLP-1 RA therapy (n = 257) from a baseline 7.8% (62 mmol/mol) in both to 6.7% (50 mmol/mol) and 7.4% (57 mmol/mol), respectively, at 26 weeks (least squares mean difference −0.6%; P < 0.0001). More iGlarLixi patients achieved HbA1c CONCLUSIONS Switching to iGlarLixi improves glucose control for patients with type 2 diabetes insufficiently controlled on a maximum tolerated dose of a GLP-1 RA plus oral antihyperglycemic agents.

Canagliflozin is a sodium glucose co-transporter 2 (SGLT2) inhibitor that reduces blood glucose, as well as blood pressure, body weight, and albuminuria in patients with type 2 diabetes mellitus (T2DM). In the CANagliflozin cardioVascular Assessment Study (CANVAS) Program, patients with T2DM and high cardiovascular risk treated with canagliflozin had a significantly lower risk of the composite outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke; hospitalization for heart failure; and renal outcomes, but also a greater risk of lower-limb amputation. Cardiovascular outcomes trials of some other T2DM agents (i.e., empagliflozin, dapagliflozin, liraglutide, semaglutide, albiglutide) have also shown potential cardiovascular and renal benefits. As a result, diabetes treatment guidelines have begun to incorporate consideration of cardiovascular and renal benefits into their treatment recommendations. Antihyperglycemic agents with proven beneficial cardiovascular effects represent a new opportunity for the diabetologist and cardiologist, in the setting of a multidisciplinary approach, to concomitantly improve glycemic control and reduce the risk of cardiovascular events in patients with T2DM. This review briefly discusses the pharmacology of canagliflozin, including clinical and preclinical data; it also describes the effects of canagliflozin on cardiovascular outcomes and side-effects, and compares these effects with other glucose-lowering agents with proven cardiovascular benefits.

This review summarizes recent cardiovascular outcome trials (CVOTs) with glucose-lowering drugs. The majority of recent CVOTs with glucose-lowering drugs have tested dipeptidyl peptidase-4 inhibitors (DPP4-i), glucagon-like peptide-1 receptors agonists (GLP1-RA), and sodium-glucose cotransporter 2 inhibitors (SGLT2i), but studies have also been performed with other agents including thiazolidinediones and insulin. All CVOTs with DPP4-I, GLP1-RA, and SGLT2-i have demonstrated the cardiovascular (CV) safety of these agents compared to usual care. However, certain GLP1-RAs (liraglutide, subcutaneous semaglutide, albiglutide, dulaglutide) and SGLT2-i (empagliflozin, canagliflozin) have demonstrated a CV benefit, showing significant reductions in composite cardiovascular outcomes. Furthermore, all SGLT2-i also significantly decreased the risk for hospitalization for heart failure. Results from these studies have altered clinical guidelines worldwide and have resulted in new indications for some glucose-lowering drugs. In patients with T2D and high risk for CVD, GLP-1RA or SGLT2-i with proven cardiovascular benefit are recommended, irrespective of glycemic control.

Background 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.). Scope of review To summarize current knowledge about GLP-1 receptor agonist. Major conclusions 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., Highlights • The GLP-1 receptor agonists class comprises seven compounds/preparations with a similar mode of action. • GLP-1 receptor agonists differ with respect to pharmacokinetic properties, duration of action, and clinical effectiveness. • Plasma glucose is lowered by effects on insulin and glucagon secretion, and by decelerating gastric emptying. • GLP-1 receptor agonists lower body weight by their influence on the central nervous system. • GLP-1 R reduce cardiovascular events (myocardial infarction, stroke, and associated mortality).

To exclude an excess risk of cardiovascular (CV) events, CV outcomes trials (CVOTs) have assessed the effects of new glucose-lowering therapies, including glucagon-like peptide-1 receptor agonists (GLP-1RAs), in patients with type 2 diabetes and established CV disease or CV risk factors. The CV safety of semaglutide vs. placebo, when added to standard care, was evaluated in the SUSTAIN 6 trial for the formulation administered once-weekly subcutaneously and in PIONEER 6 for the new once-daily oral formulation. In SUSTAIN 6 and PIONEER 6, both powered to demonstrate noninferiority (upper 95% confidence interval [CI] of the hazard ratio [HR] via risk factor modification and direct effects via GLP-1 receptors in the CV system have been proposed to be responsible for CV event reductions. The exact mechanism(s) remains to be characterized, but appears to be mainly linked to anti-atherosclerotic effects. Further research is needed to elucidate the relevant mechanisms for CV benefits of GLP-1RAs.

Altres ajuts: IM has received consultancy fess or lecture honoraria from Boerhinger Ingelheim, Eli Lilly, MSD, Novo Nordisk, Sanofi-Aventis and Astra-Zeneca and has participated in clinical trials funded by Sanofi-Aventis. AP has received consultancy fess or lecture honoraria from GSK, Boerhinger Ingelheim, Eli Lilly, Menarini, Merk, MSD, Novartis, Novo Nordisk, Pfizer, Sanofi-Aventis, AstraZeneca, Almirall and Esteve and has participated in clinical trials funded by GSK, Sanofi-Aventis, Almirall, Esteve. Several GLP-1 receptor agonists are currently available for treatment of type 2 diabetic patients. Based on their pharmacokinetic/pharmacodynamic profile, these drugs are classified as short-acting GLP-1 receptor agonists (exenatide and lixisenatide) or long-acting GLP-1 receptor agonists (exenatide-LAR, liraglutide, albiglutide, and dulaglutide). In clinical practice, they are also classified as basal or prandial GLP-1 receptor agonists to differentiate between patients who would benefit more from one or another based on characteristics such as previous treatment and the predominance of fasting or postprandial hyperglycemia. In the present article we examine available data on the pharmacokinetic characteristics of the various GLP-1 agonists and compare their effects with respect to the main parameters used to evaluate glycemic control. The article also analyzes whether the differences between the different GLP-1 agonists justify their classification as basal or prandial.

Background Suboptimal medication adherence has been associated with increased resource utilisation and mortality among patients with type 2 diabetes (T2D). Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are becoming increasingly important in the treatment of T2D. However, medications in this class differ considerably in their dosing frequency, which may impact adherence. We sought to perform a meta-analysis to compare adherence to injectable GLP-1RAs dosed once weekly vs once daily in patients with T2D. Methods Medline and Scopus were searched from 1/2005 to 7/2020 using keywords and MeSH terms pertaining to adherence and GLP-1RAs. Studies of adults with T2D were included if they compared adherence (as measured by proportion of days covered [PDC]) to injectable GLP-1RAs dosed once weekly vs once daily. A meta-analysis of non-overlapping studies was performed to evaluate the primary outcome of non-adherence, defined as the proportion of patients with a PDC Results A total of 7 studies evaluating 75 159 patients (range: 2886-30 097) with T2D were included. The follow-up periods of included studies ranged from 6 to 12 months. Injectable GLP-1RAs dosed once weekly were either dulaglutide, albiglutide or exenatide extended release; while liraglutide was the injectable once daily agent evaluated in all included studies. Upon meta-analysis, once weekly GLP-1RA dosing was associated with an 11% lower risk of non-adherence compared to once daily dosing (risk ratio = 0.89; 95% confidence interval = 0.83-0.95; I2 = 89%). Conclusion Once weekly dosing of injectable GLP-1RAs was associated with better adherence vs once daily dosing among patients with T2D. These findings coupled with the known detrimental consequences of non-adherence suggest that dosing frequency is an important factor to consider when selecting a GLP-1RA.

Results from cardiovascular (CV) outcome trials have revealed important insights into the CV safety and efficacy of glucose-lowering agents, including dipeptidyl peptidase-4 inhibitors (DPP-4i) and glucagon-like peptide-1 receptor agonists (GLP-1RA). Among patients with T2DM, DPP-4i have no significant effect on risk of major adverse CV events (MACE: CV death, myocardial infarction, or stroke) with mixed results regarding risk for heart failure (HF). While sitagliptin and linagliptin have neutral effects on HF risk, saxagliptin significantly increases the risk of HF. The CV safety of the GLP-1RA class of medications has been clearly demonstrated, and select agents, such as liraglutide, semaglutide, albiglutide, and dulaglutide, reduce the risk of MACE in patients with T2DM and established CV disease. CV outcome trials have demonstrated CV safety but not incremental efficacy for DPP-4i in most cases. Select GLP-1RA have proven efficacy for MACE and should be considered by cardiologists for CV risk mitigation in the care of patients with T2DM and established CV disease.

Cardiovascular disease (CVD) is a common and serious comorbidity of type 2 diabetes mellitus (T2DM), and cardiovascular (CV) risk assessment has become an important aspect of evaluating new therapies for T2DM before approval by the FDA. Since 2008, in order to establish safety, new therapies for T2DM have been required to demonstrate that they will not result in an unacceptable increase in CV risk. Studies performed for this purpose are termed CV outcome trials, or CVOTs. This article reviews CVOTs completed to date for the class of long-acting glucagon-like peptide-1 receptor agonists (GLP-1RAs; liraglutide, exenatide extended-release, albiglutide, dulaglutide, semaglutide injectable, semaglutide oral) and implications for clinical management of T2DM. All CVOTs have confirmed long-acting GLP-1RAs to be noninferior to (not worse than) placebo with regard to first occurrence of a primary outcome of three-point major adverse cardiovascular events (MACE; composite outcome of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke). Further, a number of the studies demonstrated a statistically significant reduction in primary outcomes of three-point MACE with GLP-1RA treatment compared with placebo. As a result, the product labeling for liraglutide, semaglutide injectable, and dulaglutide has been updated with an indication for reducing the risk of MACE in adults with T2DM and established CVD (all) or multiple CV risk factors (dulaglutide only). These findings have brought about an exciting paradigm shift from concern about not inflicting CV harm to the exciting prospect of reducing risks of CV outcomes. Major diabetes care guidelines now encourage early consideration of GLP-1RA use in patients with atherosclerotic CVD.

Aim An association between Glucagon-Like Peptide-1 Receptor Agonists (GLP1-RA) and risk of pancreatitis and pancreatic cancer has been suggested. Since its first description, several new trials (including three cardiovascular outcome trials) have been published, substantially increasing the available data set. This suggests the need for an update of the previous meta analysis. Materials and methods A Medline search for GLP-1 receptor agonists (exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, or semaglutide) was performed, collecting all randomized clinical trials, with duration ≥52 weeks, enrolling patients with type 2 diabetes, and comparing a GLP-1 receptor agonist with placebo or any other non-GLP-1 receptor agonist drug. The endpoints were pancreatitis, pancreatic cancer reported as serious adverse events. Mantel-Haenszel odds ratio (MH-OR) with 95% Confidence Interval (95% CI) was calculated for all outcomes defined above, on an intention-to-treat basis. Results A total of 43 trials fulfilling inclusion criteria (all reporting data on pancreatitis and pancreatic cancer) was identified. GLP-1 RA showed no association with pancreatitis (MH-OR 1.24 [0.94, 1.64]; p=0,13) and pancreatic cancer (MH-OR 1.28 [0.87, 1.89]; p=0,20). Conclusions No clear evidence of risk for pancreatitis was observed, whereas data on pancreatic cancer are too scarce to draw any conclusion.

The comparative efficacy of different glucagon-like peptide 1 receptor agonists and sodium glucose cotransporter 2 inhibitors for prevention of major adverse cardiovascular events (MACE) in type 2 diabetes with or without cardiorenal disease is undefined. PubMed and Embase were searched for relevant randomized trials. We conducted network meta-analysis within the Bayesian framework. Effect sizes were measured using hazard ratio (HR) and 95% confidence interval (CI). We calculated surface under the cumulative ranking curve (SUCRA) values to rank drug interventions for different type 2 diabetic subgroups. Albiglutide (HR 0.76, 95% CI 0.63-0.93) and subcutaneous semaglutide (HR 0.71, 95% CI 0.52-0.95), with the maximum SUCRA values, significantly reduced MACE versus lixisenatide in people with diabetes with cardiovascular disease; albiglutide (HRs: 0.69 and 0.72), with the maximum SUCRA value, significantly reduced MACE versus dapagliflozin and exenatide in people with diabetes with heart failure; and canagliflozin (HRs: 0.72 and 0.72) and liraglutide (HRs: 0.68 and 0.68), with the maximum SUCRA values, significantly reduced MACE versus exenatide and lixisenatide in people with diabetes with chronic kidney disease. In preventing MACE in type 2 diabetes, subcutaneous semaglutide and albiglutide are most effective for diabetes with cardiovascular disease, albiglutide is most effective for diabetes with heart failure, and canagliflozin and liraglutide are most effective for diabetes with chronic kidney disease.

Glucagon-like peptide 1 (GLP-1) receptor agonists are relatively new additions to the treatment options available for type 2 diabetes. These agents provide glycemic control by increasing glucose-dependent insulin secretion, decreasing inappropriate glucagon secretion, slowing gastric emptying, and increasing satiety (1). The GLP-1 receptor agonists are an attractive treatment option because they are associated with weight loss and have a low risk of hypoglycemia. However, their use is limited in some patients because of gastrointestinal adverse effects (nausea, vomiting, diarrhea), cost, and their subcutaneous route of administration (1). There are currently six GLP-1 receptor agonists approved for use in the United States: exenatide (Byetta), 2005; liraglutide (Victoza), 2010; exenatide XR (Bydureon), 2012; albiglutide (Tanzeum), 2014; dulaglutide (Trulicity), 2014; and lixisenatide (Adlyxin), 2016. Many differences exist within this class of medications, including efficacy and safety profiles, dosing schedules, and preparation and administration requirements, making product selection and use potentially confusing for both health care professionals (HCPs) and patients. Dosing schedule is one important consideration when comparing GLP-1 receptor agonists. Whereas three of the GLP-1 receptor agonists are available in multi-use, disposable pen devices and are given either twice daily (exenatide) or once daily (liraglutide and lixisenatide), the other three GLP-1 receptor agonists are once-weekly formulations available in single-use, disposable pen devices (albiglutide [2], dulaglutide [3], and exenatide XR [4]). Once-weekly products may offer the advantage of better adherence and ease of use compared to once- or twice-daily medications. In clinical studies, adherence to treatment and treatment satisfaction significantly increased with once-weekly GLP-1 receptor agonists compared to once- or twice-daily GLP-1 receptor agonists (5–7). In comparing efficacy and safety of the once-weekly agents, meta-analyses and head-to-head trials demonstrate that dulaglutide showed the greatest reduction in A1C compared with other once-weekly GLP-1 receptor agonists, …

Type 2 diabetes (T2D) carries risks of both cardiovascular (CV) (myocardial infarction, stroke, and peripheral vascular disease) and microvascular (retinopathy/nephropathy/neuropathy) complications. Glucose-lowering is an effective strategy for preventing microvascular complications, but the extent to which it can reduce CV complications is less certain. Glucagon-like peptide-1 (GLP-1) agonists are potent glucose-lowering agents but also have potentially beneficial effects on other traditional (body weight, blood pressure (BP), and LDL cholesterol) and non-traditional risk factors (low grade inflammation and endothelial dysfunction). The results of four large CV outcome trials with GLP-1 agonists are now available. These have compared lixisenatide (ELIXA), liraglutide (LEADER), semaglutide (SUSTAIN-6), and long-acting exenatide (EXSCEL) with placebo and standard of care over 2–4 years; four others (including with dulaglutide and albiglutide) are ongoing. LEADER and SUSTAIN-6 have demonstrated reductions in rates of major adverse CV events with active GLP-1 treatment but ELIXA and EXSCEL have not. In this review, we discuss the mechanisms by which GLP-1 receptor agonists act on the CV system and the design and conduct of these trials. Contrary to the assertions that (a) all GLP-1 agonists reduce CV disease in T2D but to different extents or (b) the magnitude of CV protection is predominantly related to glucose-lowering, we argue that CV benefit is specific to agents that provide longer acting agonism at the GLP-1 receptor. The mechanisms involve reduction in body weight and BP, and lowering of LDL-cholesterol and glucose, but pleiotropic effects—including suppression of low grade inflammation, vasodilation, and natriuresis—are also likely relevant.

Glucagon-like peptide 1 receptor agonists (GLP-1 RA) represent an integral part of the arsenal used in clinical practice to improve cardiovascular outcomes in patients with diabetes. Large-scale randomized controlled trials have shown that liraglutide, dulaglutide, albiglutide, and semaglutide all reduce the risk of cardiovascular events in patients with diabetes and either established atherosclerotic cardiovascular disease (ASCVD) or high-risk characteristics (1–4). In contrast, exenatide and lixisenatide improved glycemic control but did not have a sizable impact on cardiovascular events in clinical trials (5,6), suggesting that glycemic control and cardiovascular outcomes are at least partly uncoupled. A meta-analysis including 42,920 participants from five randomized trials demonstrated that GLP-1 RA as a drug class are associated with a significant 13% reduction in the risk of the composite of myocardial infarction, stroke, or cardiovascular death in patients with diabetes and established ASCVD (7). GLP-1 RA are recommended in patients with diabetes and established ASCVD or at high risk of ASCVD (8). They are also indicated as second-line therapy in patients without ASCVD (or without indicators of high risk) who do not meet treatment goals with lifestyle modifications and metformin alone, and they are preferred to insulin if injectable therapy is needed (8). Although the …

Albiglutide is a long acting GLP-1 receptor agonist (GLP-1 RA) administered by weekly injection and approved for use in type 2 diabetes. It has less gastrointestinal side effects than other GLP-1 RAs in current use but does not improve HbA1c or promote weight loss to the same extent as some competitor agents. Area covered: The current use of albiglutide is discussed. The review encompassed a search of PubMed and a thorough analysis of the European Union and US Food and Drug Administration approval documents. Expert opinion: Unlike competitor agents, the gastrointestinal side effects of albiglutide are not much greater than placebo. It has been studied and appears safe at all stages of renal failure. There exists concern about an imbalance of pancreatitis cases in the approval program as well as injection site reactions which led to discontinuance of therapy in up to 2% of participants. A large long-term study is now underway to determine if albiglutide, with its relatively favorable GI tolerance, has a place in the treatment of patients with increased risk of cardiovascular events. At present, albiglutide is a safe agent to introduce GLP-1 RA treatment into the regimen for type 2 diabetes patients and may be the GLP-1 agent of choice in patients with renal insufficiency.

Aims/Introduction The present phase 3, randomized, double-blind 24-week study with extension to 1 year assessed the efficacy and safety of albiglutide compared with placebo in Japanese patients with type 2 diabetes mellitus inadequately controlled by diet and exercise with or without a single oral antidiabetic drug. Materials and Methods Patients received weekly albiglutide 30 mg (n = 160), albiglutide 50 mg (n = 150) or a placebo switched to albiglutide 30 mg after 24 weeks (n = 77). Open-label daily liraglutide 0.9 mg (n = 103) was included as a reference. Oral antidiabetic drug use was discontinued before baseline. The primary end-point was 24-week change from baseline in glycated hemoglobin (HbA1c). Secondary end-points included fasting plasma glucose, bodyweight and adverse events. Results At 24 weeks, mean HbA1c changes from baseline were −1.10, −1.30, and 0.25% for albiglutide 30, 50 mg and placebo, respectively (P vs placebo