Long-acting GLP-1 Research Articles

Occurrence of nausea, vomiting and diarrhoea reported as adverse events in clinical trials studying glucagon-like peptide-1 receptor agonists: A systematic analysis of published clinical trials.

GLP-1 receptor agonists (RAs) may cause nausea, vomiting or diarrhoea. The aim of this study was to assess the risk of adverse events (AEs) with GLP-1 RAs and their relation to dose, background medication and duration of action. The PubMed database was searched and 32 clinical trials with GLP-1 RAs (phase 3) were selected. We performed a systematic analysis and compared the proportion of patients reporting nausea, vomiting or diarrhoea, for different doses and glucose-lowering background medications, and relative to a reference compound within the subclasses of short- (exenatide b.i.d.) and long-acting (liraglutide) GLP-1 RAs, calculating the relative risks ± 95% confidence intervals. The risk of nausea was dose-dependent for long-acting (P = .0063) and across all GLP-1 RAs (P = .0017), and a similar trend was observed for vomiting (P = .23). Diarrhoea was dose-dependent (P = .031). Background treatment with metformin was associated with more nausea (P = .04) and vomiting (P = .0009). Compared to exenatide b.i.d., there was less nausea and diarrhoea with lixisenatide. Compared to liraglutide, there was a similar risk associated with dulaglutide, and less with exenatide q.w. and albiglutide. Long-acting GLP-1 RAs were associated with less nausea and vomiting, but with more diarrhoea than short-acting agents. GLP-1 RAs are associated with gastrointestinal AEs that are related to dose and background medications (especially metformin) and may vary in a compound-specific manner. Long-acting agents are associated with less nausea and vomiting but with more diarrhoea.

A meta-analysis comparing clinical effects of short- or long-acting GLP-1 receptor agonists versus insulin treatment from head-to-head studies in type 2 diabetic patients.

To study differences in clinical outcomes between initiating glucagon-like peptide-1 receptor agonist (GLP-1 RAs) vs insulin treatment in patients with type 2 diabetes treated with oral glucose-lowering medications (OGLM). Prospective, randomized trials comparing GLP-1 RA and insulin treatment head-to-head as add-on to OGLM were identified (PubMed). Differences from baseline values were compared for HbA1c, fasting plasma glucose, bodyweight, blood pressure, heartrate and lipoproteins. Proportions of patients reporting hypoglycaemic episodes were compared. Of 712 publications identified, 23 describing 19 clinical trials were included in the meta-analysis. Compared to insulin, GLP-1 RAs reduced HbA1c more effectively (Δ -.12%, P < .0001). Basal insulin was more effective in reducing fasting plasma glucose (Δ -1.8 mmol/L, P < .0001). GLP-1 RAs reduced bodyweight more effectively (Δ -3.71 kg; P < .0001). The proportion of patients experiencing hypoglycaemic episodes was 34% lower with GLP-1 RAs ( P < .0001), with a similar trend for severe hypoglycaemia. Systolic blood pressure was lower and heartrate was higher with GLP-1 RAs ( P < .0001). Triglycerides and LDL cholesterol were significantly lower with GLP-1 RAs. Long-acting GLP-1 RAs were better than short-acting GLP-1 RAs in reducing HbA1c and fasting glucose, but were similar regarding bodyweight. Slightly better glycaemic control can be achieved by adding GLP-1 RAs to OGLM as compared to insulin treatment, with added benefits regarding bodyweight, hypoglycaemia, blood pressure and lipoproteins. These differences are in contrast to the fact that insulin is prescribed far more often than GLP-1 RAs.

Glucose enhances rat islet function via stimulating CART expression

Cocaine- and amphetamine-regulated transcript (CART) is an anorexigenic peptide widely expressed in the central and peripheral nervous systems, as well as in endocrine cells. CART is markedly upregulated in the β-cells of several rodent models of type-2 diabetes. The stimulatory effect of exogenous CART peptide on insulin secretion is cAMP dependent. Glucose is the most important regulator of islet function. However, the role of CART in glucose-potentiated insulin secretion remains unclear. Here, our results showed that glucose time- and dose-dependently elicited CART mRNA expression in rat islets. Both the glucokinase agonist GKA50 and the long-acting GLP-1 analogue exendin-4 increased CART mRNA expression. The protein kinase A (PKA) inhibitor H89 and the inactivation of cAMP response element-binding protein (CREB) suppressed forskolin-stimulated CART mRNA expression. Furthermore, CART overexpression amplified insulin secretion from rat islets in response to glucose and forskolin, and ameliorated dexamethasone-impaired insulin secretion. These findings suggest that islet-derived CART is involved, at least in part, in high glucose-potentiated pancreatic β-cell function.

A real world experience of long-acting GLP-1 receptor agonists in a medical center in southern of Taiwan

A real world experience of long-acting GLP-1 receptor agonists in a medical center in southern of Taiwan

New Approaches to Feline Diabetes Mellitus: Glucagon-like peptide-1 analogs.

Incretin-based therapies are revolutionizing the field of human diabetes mellitus (DM) by replacing insulin therapy with safer and more convenient long-acting drugs. Incretin hormones (glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic peptide [GIP]) are secreted from the intestinal tract in response to the presence of food in the intestinal lumen. GLP-1 delays gastric emptying and increases satiety. In the pancreas, GLP-1 augments insulin secretion and suppresses glucagon secretion during hyperglycemia in a glucose-dependent manner. It also protects beta cells from oxidative and toxic injury and promotes expansion of beta cell mass. Clinical data have revealed that GLP-1 analog drugs are as effective as insulin in improving glycemic control while reducing body weight in people suffering from type 2 DM. Furthermore, the incidence of hypoglycemia is low with these drugs because of their glucose-dependent mechanism of action. Another significant advantage of these drugs is their duration of action. While insulin injections are administered at least once daily, long-acting GLP-1 analogs have been developed as once-a-week injections and could potentially be administered even less frequently than that in diabetic cats. This article reviews the physiology of incretin hormones, and the pharmacology and use of GLP-1 analogs, with emphasis on recent research in cats. Further therapies that are based on incretin hormones, such as DPP-4 inhibitors, are also briefly discussed, as are some other treatment modalities that are currently under investigation.

The Neuroprotection of Liraglutide Against Ischaemia-induced Apoptosis through the Activation of the PI3K/AKT and MAPK Pathways.

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that increases glucose-dependent insulin secretion to reduce the glucose level. Liraglutide, a long-acting GLP-1 analogue, has been found to have neuroprotective action in various experimental models. However, the protective mechanisms of liraglutide in ischaemic stroke remain unclear. Here, we demonstrated that liraglutide significantly decreased the infarct volume, improved neurologic deficits, and lowered stress-related hyperglycaemia without causing hypoglycaemia in a rat model of middle cerebral artery occlusion (MCAO). Liraglutide inhibited cell apoptosis by reducing excessive reactive oxygen species (ROS) and improving the function of mitochondria in neurons under oxygen glucose deprivation (OGD) in vitro and MCAO in vivo. Liraglutide up-regulated the phosphorylation of protein kinase B (AKT) and extracellular signal-regulated kinases (ERK) and inhibited the phosphorylation of c-jun-NH2-terminal kinase (JNK) and p38. Moreover, the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 and/or the ERK inhibitor U0126 counteracted the protective effect of liraglutide. Taken together, these results suggest that liraglutide exerts neuroprotective action against ischaemia-induced apoptosis through the reduction of ROS and the activation of the PI3K/AKT and mitogen-activated protein kinase (MAPK) pathways. Therefore, liraglutide has therapeutic potential for patients with ischaemic stroke, especially those with Type 2 diabetes mellitus or stress hyperglycaemia.

Effects of the Novel Long-Acting GLP-1 Agonist, Albiglutide, on Cardiac Function, Cardiac Metabolism, and Exercise Capacity in Patients With Chronic Heart Failure and Reduced Ejection Fraction

ObjectivesThis study sought to determine if glucagon-like peptide (GLP)-1 ameliorates myocardial metabolic abnormalities in chronic heart failure. BackgroundAlbiglutide (GSK716155) is a GLP-1 agonist indicated for type 2 diabetes. MethodsWe performed a randomized, placebo-controlled study evaluating 12 weeks of albiglutide in New York Heart Association II or III subjects with ejection fraction <40%. Subjects received weekly placebo (n = 30) or albiglutide 3.75 mg (n = 12), 15 mg (n = 13), or 30 mg (n = 27). The primary comparison was between albiglutide 30 mg and placebo. Assessments included echocardiography, 6-minute-walk test, and peak oxygen consumption. In a subgroup of patients, myocardial glucose and oxygen use were assessed. Endpoints are reported as change from baseline ± SE. ResultsAlbiglutide 30 mg compared with placebo did not improve change from baseline in left ventricular ejection fraction (2.4% [1.1%] vs. 4.4% [1.1%]; p = 0.22), 6-min walk test (18 [12] m vs. 9 [11] m; p = 0.58), myocardial glucose use (p = 0.59), or oxygen use (p = 0.25). In contrast, albiglutide 30 mg versus placebo improved change from baseline in peak oxygen consumption (0.9 [0.5] ml/kg/min vs. -0.6 [0.5] ml/kg/min; p = 0.02). Albiglutide was well tolerated. ConclusionsAlthough there was no detectable effect of albiglutide on cardiac function or myocardial glucose use, there was a modest increase in peak oxygen consumption, which could have been mediated by noncardiac effects. (A Multi-center, Placebo-controlled Study to Evaluate the Safety of GSK716155 and Its Effects on Myocardial Metabolism, Myocardial Function, and Exercise Capacity in Patients With NYHA Class II/III Congestive Heart Failure; NCT01357850)

Hydrogel Drug Delivery System Using Self-Cleaving Covalent Linkers for Once-a-Week Administration of Exenatide.

We have developed a unique long-acting drug-delivery system for the GLP-1 agonist exenatide. The peptide was covalently attached to Tetra-PEG hydrogel microspheres by a cleavable β-eliminative linker; upon s.c. injection, the exenatide is slowly released at a rate dictated by the linker. A second β-eliminative linker with a slower cleavage rate was incorporated in polymer cross-links to trigger gel degradation after drug release. The uniform 40 μm microspheres were fabricated using a flow-focusing microfluidic device and in situ polymerization within droplets. The exenatide-laden microspheres were injected subcutaneously into the rat, and serum exenatide measured over a one-month period. Pharmacokinetic analysis showed a t1/2,β of released exenatide of about 7 days which represents over a 300-fold half-life extension in the rat and exceeds the half-life of any currently approved long-acting GLP-1 agonist. Hydrogel-exenatide conjugates gave an excellent Level A in vitro-in vivo correlation of release rates of the peptide from the gel, and indicated that exenatide release was 3-fold faster in vivo than in vitro. Pharmacokinetic simulations indicate that the hydrogel-exenatide microspheres should support weekly or biweekly subcutaneous dosing in humans. The rare ability to modify in vivo pharmacokinetics by the chemical nature of the linker indicates that an even longer acting exenatide is feasible.

Neurobehavioral effects of liraglutide and sitagliptin in experimental models

Glucagon-like peptide (GLP-1) receptor agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors are two currently approved therapies for type 2 diabetes mellitus (T2DM). Present study evaluated the effect of liraglutide (a long-acting GLP-1 agonist) and sitagliptin (a DPP-4 inhibitor) on nociception, anxiety, depression-like behavior and cognition in rats or mice.Nociception was assessed using tail-flick test; anxiety-behavior in open-field test and elevated plus maze (EPM) test while depression-like behavior was evaluated in forced swim test (FST) and tail-suspension test (TST). Cognition was assessed in EPM and Morris water maze (MWM) following memory deficit induced by pentylenetetrazole (PTZ) or scopolamine.In tail-flick test sitagliptin (6mg/kg) produced transient nociceptive effect. Liraglutide (200µg/kg) reduced peripheral square crossings by rats in open field test as well as reduced closed arm entries in the EPM, indicating a decline in exploratory behavior. In FST and TST models for depression, the duration of immobility with sitagliptin (6mg/kg) was reduced significantly in comparison to control group suggesting its antidepressant effect. Liraglutide did not show any antidepressant action. In EPM test for cognition, liraglutide and sitagliptin ameliorated the increase in transfer latency caused by PTZ in a dose-dependent manner. In MWM liraglutide and sitagliptin prevented the scopolamine-induced increase of the escape latency.This study shows that sitagliptin has mild antinociceptive effect and anti-depressant effect in the animal models of depression while liraglutide did not have such an effect. Liraglutide showed anxiogenic effects in the animal models. Both liraglutide and sitagliptin produced cognitive improvement in the animal models.

Basal and stimulated calcitonin levels in patients with type 2 diabetes did not change during 1 year of Liraglutide treatment

Background and aimsThe administration of Liraglutide, a long-acting GLP-1 receptor (GLP-1R) agonist, is associated with C-cell adenomas and carcinomas in rats. In humans, GLP-1R is highly expressed in C-cells hyperplasia (CCH) and in medullary thyroid cancer (MTC), though no changes in basal serum calcitonin (bCT) levels were recorded in type 2 diabetic (T2DM) patients treated with Liraglutide. To diagnose the possible development of CCH during Liraglutide treatment, we evaluated CT levels stimulated by calcium test (sCT). Materials and methodsbCT and sCT and metabolic and anthropometric parameters were evaluated in 26 T2DM patients at baseline and at 1, 3, 6 and 12months of treatment. ResultsIn all patients, bCT remained within the normal range during the entire study period. In females and males, the higher sCT values were reached after 3months and 1month, respectively, with a progressive reduction at 6–12months. The greater decrease of HbA1c values was reached at 3months, while body weight and waist circumference decreased over the first 4weeks of therapy. Lipase levels significantly increased, with a peak value at 1month. ConclusionThe chronic administration of Liraglutide did not lead to statistically significant variations in both bCT and sCT. Stimulated CT levels increased, though always below the normal range, during the first 1–3months of treatment, and progressively decreased to baseline levels. This finding is consistent with the effects recorded at the glycometabolic level, and suggests the possible induction of a drug tolerance involving also the C cells and thus preventing CCH.

GLP-1 Receptor Agonist Treatment Increases Bone Formation and Prevents Bone Loss in Weight-Reduced Obese Women.

Recent studies indicate that glucagon-like peptide (GLP)-1 regulates bone turnover, but the effects of GLP-1 receptor agonists (GLP-1 RAs) on bone in obese weight-reduced individuals are unknown. To investigate the role of GLP-1 RAs on bone formation and weight loss-induced bone mass reduction. Randomized control study. Outpatient research hospital clinic. Thirty-seven healthy obese women with body mass index of 34 ± 0.5 kg/m(2) and age 46 ± 2 years. After a low-calorie-diet-induced 12% weight loss, participants were randomized to treatment with or without administration of the GLP-1 RA liraglutide (1.2 mg/d) for 52 weeks. In case of weight gain, up to two meals per day could be replaced with a low-calorie-diet product to maintain the weight loss. Total, pelvic, and arm-leg bone mineral content (BMC) and bone markers [C-terminal telopeptide of type 1 collagen (CTX-1) and N-terminal propeptide of type 1 procollagen (P1NP)] were investigated before and after weight loss and after 52-week weight maintenance. Primary endpoints were changes in BMC and bone markers after 52-week weight maintenance with or without GLP-1 RA treatment. Total, pelvic, and arm-leg BMC decreased during weight maintenance in the control group (P < .0001), but not significantly in the liraglutide group. Thus, total and arm-leg BMC loss was four times greater in the control group compared to the liraglutide group (estimated difference, 27 g; 95% confidence interval, 5-48; P = .01), although the 12% weight loss was maintained in both groups. In the liraglutide group, the bone formation marker P1NP increased by 16% (7 ± 3 μg/L) vs a 2% (-1 ± 4 μg/L) decrease in the control group (P < .05). The bone resorption marker CTX-1 collagen did not change during the weight loss maintenance phase. Treatment with a long-acting GLP-1 RA increased bone formation by 16% and prevented bone loss after weight loss obtained through a low-calorie diet, supporting its role as a safe weight-lowering agent.

Glucagon-like polypeptide agonists in type 2 diabetes mellitus: efficacy and tolerability, a balance.

Glucagon-like polypeptide (GLP-1) receptor agonist treatment has multiple effects on glucose metabolism, supports the β cell, and promotes weight loss. There are now five GLP-1 agonists in clinical use with more in development. GLP-1 treatment typically can induce a lowering of hemoglobin A1c (HbA1c) of 0.5-1.5% over time with weight loss of 2-5%. In some individuals, a progressive loss of weight occurs. There is evidence that GLP-1 therapy opposes the loss of β cells which is a feature of type 2 diabetes. The chief downside of GLP-1 treatment is the gastrointestinal motility disturbance which is one of the modes of action of the hormone; significant nausea, vomiting, and diarrhea may lead to discontinuation of treatment. Although daily injection of GLP-1 agents is successful, the development of extended release preparations allows for injection once weekly, and perhaps much longer in the future. The indication for GLP-1 use is diabetes, but now, liraglutide has been approved for primary treatment of obesity. When oral agents fail to control glucose levels in type 2 diabetes, there is a choice between long-acting insulin and GLP-1 agonists as additional treatments. The lowering of HbA1c by either modality is equivalent in most studies. Patients lose weight with GLP-1 treatment and gain weight on insulin. There is a lower incidence of hypoglycemia with GLP-1 therapy but a much higher incidence of gastrointestinal complaints. Insulin dosing is flexible while GLP-1 agents have historically been administered at fixed dosages. Now, the use of combined long-acting insulin and GLP-1 agonists is promising a major therapeutic change. Combined therapy takes advantage of the benefits of both insulin and GLP-1 agents. Furthermore, direct admixture of both in the same syringe will permit flexible dosing, improvement of glucose levels, and reduction of both hypoglycemia and gastrointestinal side effects.

Chronic Toxicity and Carcinogenicity Studies of the Long-Acting GLP-1 Receptor Agonist Dulaglutide in Rodents.

The tumorigenic potential of dulaglutide was evaluated in rats and transgenic mice. Rats were injected sc twice weekly for 93 weeks with dulaglutide 0, 0.05, 0.5, 1.5, or 5 mg/kg corresponding to 0, 0.5, 7, 20, and 58 times, respectively, the maximum recommended human dose based on plasma area under the curve. Transgenic mice were dosed sc twice weekly with dulaglutide 0, 0.3, 1, or 3 mg/kg for 26 weeks. Dulaglutide effects were limited to the thyroid C-cells. In rats, diffuse C-cell hyperplasia and adenomas were statistically increased at 0.5 mg/kg or greater (P ≤ .01 at 5 mg/kg), and C-cell carcinomas were numerically increased at 5 mg/kg. Focal C-cell hyperplasia was higher compared with controls in females given 0.5, 1.5, and 5 mg/kg. In transgenic mice, no dulaglutide-related C-cell hyperplasia or neoplasia was observed at any dose; however, minimal cytoplasmic hypertrophy of C cells was observed in all dulaglutide groups. Systemic exposures decreased over time in mice, possibly due to an antidrug antibody response. In a 52-week study designed to quantitate C-cell mass and plasma calcitonin responses, rats received twice-weekly sc injections of dulaglutide 0 or 5 mg/kg. Dulaglutide increased focal C-cell hyperplasia; however, quantitative increases in C-cell mass did not occur. Consistent with the lack of morphometric changes in C-cell mass, dulaglutide did not affect the incidence of diffuse C-cell hyperplasia or basal or calcium-stimulated plasma calcitonin, suggesting that diffuse increases in C-cell mass did not occur during the initial 52 weeks of the rat carcinogenicity study.

GLP-1 Receptor Agonists in Type 2 Diabetes and Beyond - New Insights 2015.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) were introduced for type 2 diabetes therapy nearly 10 years ago, among them short-acting compounds on the basis of the GLP-1-like peptide exendin-4 (exenatide and lixisenatide) and a long-acting GLP-1 RA based on the human GLP-1 sequence (liraglutide). Recently, two novel long-acting GLP-1 RAs on the basis of human GLP-1 sequence, for once-weekly application, have been approved for therapy of type 2 diabetes. Additionally, liraglutide has been approved for treatment of obesity at a higher dose than that used for diabetes therapy. This mini-review gives a short overview of the novel long-acting GLP-1 RAs albiglutide and dulaglutide and also reviews the studies of liraglutide in treatment of obesity leading to its approval for this use. These studies were largely presented at the annual meeting of the European Association for the Study of Diabetes (EASD) in fall 2014.

GLP-1 Receptor Agonists in Type 2 Diabetes and Beyond – New Insights 2015

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) were introduced for type 2 diabetes therapy nearly 10 years ago, among them shortacting compounds on the basis of the GLP-1-like peptide exendin-4 (exenatide and lixisenatide) and a long-acting GLP-1 RA based on the human GLP-1 sequence (liraglutide). Recently, two novel long-acting GLP-1 RAs on the basis of human GLP-1 sequence, for once-weekly application, have been approved for therapy of type 2 diabetes. Additionally, liraglutide has been approved for treatment of obesity at a higher dose than that used for diabetes therapy. This mini-review gives a short overview of the novel long-acting GLP-1 RAs albiglutide and dulaglutide and also reviews the studies of liraglutide in treatment of obesity leading to its approval for this use. These studies were largely presented at the annual meeting of the European Association for the Study of Diabetes (EASD) in fall 2014.

PEGylated exendin-4, a modified GLP-1 analog exhibits more potent cardioprotection than its unmodified parent molecule on a dose to dose basis in a murine model of myocardial infarction.

A Site-specifically PEGylated exendin-4 (denoted as PEG-Ex4) is an exendin-4 (denoted as Ex4) analog we developed by site-specific PEGylation of exendin-4 with a high molecular weight trimeric poly(ethylene glycol) (tPEG). It has been shown to possess prolonged half-life in vivo with similar receptor binding affinity compared to unmodified exendin-4 by our previous work. This study is sought to test whether PEG-Ex4 is suitable for treating myocardial infarction (MI). In the MI model, PEG-Ex4 was administered every 3 days while equivalent amount of Ex4 was administered every 3 days or twice daily. Animal survival rate, heart function, remodeling and neoangiogenesis were evaluated and compared. Tube formation was examined in endothelial cells. In addition, Western blotting and histology were performed to determine the markers of cardiac hypertrophy and angiogenesis and to explore the possible molecular mechanism involved. PEG-Ex4 and Ex4 showed comparable binding affinity to GLP-1 receptor. In MI mice, PEG-Ex4 given at 3 days interval achieved similar extent of protection as Ex4 given twice daily, while Ex4 given at 3 days interval failed to produce protection. PEG-Ex4 elevated endothelial tube formation in vitro and capillary density in the border area of MI. PEG-Ex4 increased Akt activity and VEGF production in a GLP-1R dependent manner in endothelial cells and antagonism of GLP-1R, Akt or VEGF abolished the protection of PEG-Ex4 in the MI model. PEG-Ex4 is a potent long-acting GLP-1 receptor agonist for the treatment of chronic heart disease. Its protection might be attributed to enhanced angiogenesis mediated by the activation of Akt and VEGF.

Efficacy and Safety of Once Weekly Dulaglutide vs. Once Daily Liraglutide in Type 2 Diabetes (AWARD 6)

This phase 3, randomized, open-label, parallel-arm 26-week study compared the efficacy and safety of once weekly dulaglutide (DU) 1.5 mg, a long-acting GLP-1 receptor agonist, with once daily liraglutide (LIRA) 1.8 mg in metformin-treated (≥1500 mg/day) patients with type 2 diabetes.

Basal insulin combined incretin mimetic therapy with glucagon-like protein 1 receptor agonists as an upcoming option in the treatment of type 2 diabetes: a practical guide to decision making.

The combination of basal insulin and glucagon-like protein 1 receptor agonists (GLP-1 RAs) is a new intriguing therapeutic option for patients with type 2 diabetes. In our daily practice we abbreviate this therapeutic concept with the term BIT (basal insulin combined incretin mimetic therapy) in a certain analogy to BOT (basal insulin supported oral therapy). In most cases BIT is indeed an extension of BOT, if fasting, prandial or postprandial blood glucose values have not reached the target range. In our paper we discuss special features of combinations of short- or prandial-acting and long- or continuous-acting GLP-1 RAs like exenatide, lixisenatide and liraglutide with basal insulin in relation to different glycemic targets. Overall it seems appropriate to use a short-acting GLP-1 RA if, after the near normalization of fasting blood glucose with BOT, the prandial or postprandial values are elevated. A long-acting GLP-1 RA might well be given, if fasting blood glucose values are the problem. Based on pathophysiological findings, recent clinical studies and our experience with BIT and BOT as well as BOTplus we developed chart-supported algorithms for decision making, including features and conditions of patients. The development of these practical tools was guided by the need for a more individualized antidiabetic therapy and the availability of the new BIT principle.

Albiglutide: a new GLP-1 receptor agonist for the treatment of type 2 diabetes.

To review the pharmacology, pharmacokinetics, safety, and efficacy of albiglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA) in type 2 diabetes (T2D). A MEDLINE search (1950-June 2014) was conducted using the keyword albiglutide. References were reviewed to identify additional sources. Articles evaluating pharmacokinetics, pharmacodynamics, safety, or efficacy of albiglutide were included. Albiglutide is a long-acting GLP-1 RA that lowers glycosylated hemoglobin (A1C) and reduces weight by stimulating glucose-dependent insulin secretion, suppressing glucagon secretion, delaying gastric emptying, and promoting satiety. Albiglutide has a long half-life as a result of resistance to degradation by dipeptidyl peptidase-4 and fusion to albumin, thus allowing once-weekly dosing. Albiglutide has been studied as monotherapy and add-on therapy to metformin, sulfonylureas, thiazolidinediones, insulin glargine, and varying combinations of these agents. Clinical studies have shown albiglutide to be superior to placebo, sitagliptin, and glimepiride and noninferior to insulin glargine and insulin lispro at reducing A1C in T2D patients, with A1C changes from baseline ranging from -0.55% to -0.9%. Noninferiority was not achieved when compared to liraglutide and pioglitazone. Weight changes ranged from +0.28 to -1.21 kg. The most common side effects are upper-respiratory-tract infections, diarrhea, nausea, and injection-site reactions. Albiglutide is the fourth GLP-1 RA approved in the United States. Advantages include once-weekly dosing and fewer gastrointestinal side effects compared with liraglutide, but it is less effective at reducing A1C and weight compared to liraglutide. It has not been compared head to head with other GLP-1 RAs.

Differences in acute anorectic effects of long-acting GLP-1 receptor agonists in rats

Long-acting glucagon-like peptide-1 receptor (GLP-1R) agonists have both glucose- and weight-lowering effects. The brain is poised to mediate both of these actions since GLP-1Rs are present in key areas known to control weight and glucose. Although some research has been performed on the effects of exendin-4 in the brain, little data exists on the central effects of liraglutide, a long-acting GLP-1R agonist with much closer structural homology to native GLP-1. In lean, Long-Evans rats, we found that direct intra-third cerebroventricular (i3vt) administration of 0.26nmol liraglutide caused a 50% reduction in food intake. However, exendin-4 produced the same reduction in food intake with 10-fold greater potency (0.02nmol). These data are supported by similar c-Fos immunoreactivity in the hypothalamic paraventricular nuclei by exendin-4 as compared to liraglutide despite differing doses. The anorectic effects of both drugs were blocked with i3vt pre-treatment of a GLP-1R competitive antagonist, exendin(9-39), indicating that both drugs required the GLP-1R for their effects. Exendin-4, and not liraglutide, caused hyperglycemia when given i3vt prior to an oral glucose tolerance test, although liraglutide did not lower glucose. Thus, these data show that GLP-1R agonists have differing anorectic potencies in the CNS, which may account for some of their clinical differences. Additionally, we show here that the glucose lowering properties of acute administration of GLP-1R agonists are not accounted for by their central effects.