GLP‑1 receptor agonists

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GLP 1 receptor agonists show neuroprotective effects in animal models of diabetes

GLP 1 receptor agonists show neuroprotective effects in animal models of diabetes

neuroprotective effects (Kastin et al., 2002; Kastin and Akerstrom, 2003; McClean et al., 2011; Hunter and Holscher, 2012; Christensen et al., 2015; Athauda et al., 2017). GLP-1 receptors are expressed in the brains of rodents, primates and humans (Merchenthaler et al., 1999; Cork et al., 2015; Heppner et al., 2015; Farr et al., 2016). GLP-1 receptor agonists such as exendin- 4 or liraglutide can reverse insulin de-sensitization in the brain (Bomfim et al., 2012; Long- Smith et al., 2013). The localization and distribution of the insulin receptor and increased levels of insulin receptor substrate (IRS)-1 phosphorylated at serine 616 (IRS-1 pS(616)), a key marker of insulin resistance, was normalized in the brains of mice by treatment with liraglutide (Long-Smith et al., 2013). Liraglutide also improved key biomarkers in the brains of diabetic rats. The levels of insulin found in the brain were reduced, and there was a decrease in the phosphorylation of protein kinase B (AKT) and glycogen synthase kinase-3beta (GSK-3beta), which indicated decreased insulin signaling in rats with T2DM. Liraglutide treatment not only ameliorated hyperglycemia and peripheral insulin resistance, but also reversed brain insulin de- sensitization in a time-dependent manner (Yang et al., 2013). In the STZ model, insulin signaling was re-sensitized following activation of GLP-1 receptors, as illustrated by reduction of phospho-IRS1 Ser1101 levels and by pAkt Ser473 upregulation and reactivation (Shi et al., 2017). Through GLP-1 receptor activation, cAMP/PKA/CREB growth factor signaling cascade is activated thus increasing gene expression of the insulin receptor, insulin, IRS-1, Akt and other growth factor-related proteins (Perfetti et al., 2000; Doyle and Egan, 2007; Park et al., 2010; Holscher, 2014; Talbot, 2014).
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Is there a justification for classifying GLP-1 receptor agonists as basal and prandial?

Is there a justification for classifying GLP-1 receptor agonists as basal and prandial?

As stated above, after initiation of treatment with basal insulin, which decreases fasting glucose, the rela- tive contribution of postprandial hyperglycemia to total hyperglycemia increases from 20–24% to 59–69% [4]. GLP-1 receptor agonists stimulate glucose-medicated insulin secretion, suppress glucagon secretion, delay gas- tric emptying, and decrease appetite, thus explaining the considerable effect of these drugs on postprandial hyper- glycemia and weight loss. Therefore, patients treated with basal insulin also seem to be suitable candidates for GLP-1 receptor agonists, and combining GLP-1 receptor agonists with basal insulin offers an alternative approach to intensification of insulin therapy when basal insu- lin is insufficient. Systematic reviews and meta-analyses of prospective studies [39–42] demonstrate that GLP-1 receptor agonists added to basal insulin decrease post- prandial glucose levels, HbA1c levels, body weight, and basal insulin requirements without increasing the risk of major hypoglycemic events. Randomized studies that evaluate the effect of GLP-1 receptor agonists combined with basal insulin [43–46] confirm these findings. Buse et  al. [43] found that the addition of exenatide to basal insulin led to a reduction in HbA1c that was significantly greater than with placebo (−1.74 vs −1.04%; p < 0.001), with a lower increase in the dose of insulin. In addition, data on self-monitoring of capillary glucose show signifi- cant decreases in postprandial glucose levels at breakfast and dinner. In the three Get Goal studies [44–46], addi- tion of lixisenatide to basal insulin led to an improvement in HbA1c and hyperglycemia after breakfast, as well as weight loss. In addition, some randomized controlled tri- als have compared GLP-1 receptor agonists to prandial insulin in patients treated with a basal insulin regimen. Diamant et al. [47] analyzed the addition of exenatide in patients treated with insulin glargine and found a similar reduction in HbA1c with respect to addition of insulin lispro; however, weight loss and the reduction in fast- ing plasma glucose were greater with exenatide. Mathieu et al. [48] compared the effect of liraglutide with that of single-dose insulin aspart administered with the main meal of the day in patients who had previously received insulin degludec and metformin. The results revealed a
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Optimizing the Care of Patients With Type 2 Diabetes Using Incretin-Based Therapy: Focus on GLP-1 Receptor Agonists

Optimizing the Care of Patients With Type 2 Diabetes Using Incretin-Based Therapy: Focus on GLP-1 Receptor Agonists

Another factor to consider is the slower onset of glycemic lower- ing with exenatide QW because this may compromise adherence when patients see only small changes in fasting and postprandial glucose over the first few weeks. If the delay in glycemic response with exenatide QW is an identified concern and symptoms of hyperglycemia are present, the addition of basal insulin to exenatide QW can be helpful to more quickly reduce symptoms and achieve glycemic control. Once symptoms have improved and glycemic control is achieved, it is generally possible to titrate down and discontinue the basal insulin. These scenarios are examples of how multiple factors often affect the selection of a glucose-lowering therapy for an individual patient. By considering the differences among the GLP-1 receptor agonists outlined in Table 2, therapy may individual- ized to provide each patient with the best opportunity for successful self-management.
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Extra Glycemic Impacts of GLP 1 Receptor Agonists: Benefits of a Class Effect?

Extra Glycemic Impacts of GLP 1 Receptor Agonists: Benefits of a Class Effect?

An interaction between the adipose-derived peptide, leptin, and GLP-1 has been demonstrated in experiments in rodents showing that subthreshold doses of leptin increased the ability of GLP-1 inhibit food intake. Further- more, GLP-1 receptor agonists can reinstate leptin sensitivity in obese animals. As in animals, obese humans have high levels of circulating leptin but are leptin resistant and therefore do not respond appropriately to this signal to reduce energy intake. During weight loss, a drop in plasma leptin levels that results from decreased fat mass produces a rebound response that favors increased food intake. Based on animal studies, it was postulated that administration of a GLP-1 receptor agonist during diet-induced weight loss would inhibit decreases in so- luble leptin receptor plasma concentrations (one marker for leptin activity) caused by decreased adiposity and thus prevent a regain in body weight. This study demonstrated that liraglutide (1.2 mg/day) inhibited the in- crease in soluble leptin receptor that is normally seen in individuals undergoing weight loss. Consequently, free leptin levels were increased, thereby providing a signal that would prevent an increase in food intake and a de- crease in energy expenditure. Supporting the hypothesis, the results indicated that the group receiving the lirag- lutide, in conjunction with reduced caloric intake, had greater weight loss during the maintenance period than the group that did not receive liraglutide. This study has important implications for the potential use of liraglu- tide as an adjunct to more traditional weight loss regimens and for the long-term sustainability of weight loss treatments. Additionally, it suggests another avenue through which GLP-1 receptor agonists contribute to weight loss [56].
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Choosing GLP-1 Receptor Agonists or DPP-4 Inhibitors: Weighing the Clinical Trial Evidence

Choosing GLP-1 Receptor Agonists or DPP-4 Inhibitors: Weighing the Clinical Trial Evidence

Selecting Among GLP-1 Receptor Agonists and DPP-4 Inhibitors There are numerous factors to consider when selecting among the treatment options for type 2 diabetes, including the five incretin-based therapies. These include mechanisms for regulating glucose homeostasis, magnitude of A1C reduction, effects on fasting plasma glucose (FPG) and postprandial glucose (PPG) levels, effects on pancreatic β-cell func- tion, nonglycemic effects, safety and tolerability (especially with regard to hypoglycemia), effects on weight, ease of use, and cost. To gain insight into these considerations, the subse- quent discussion will focus on seven
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GLP 1 receptor agonists for Parkinson's disease (Protocol)

GLP 1 receptor agonists for Parkinson's disease (Protocol)

A challenge for clinical trials of neurodegenerative diseases such as PD is to differentiate between the disease-modifying effects and symptomatic effects of any therapeutic agent. Scales used in clin- ical assessment of PD to measure changes in, for example, motor impairment or quality of life, are unable to distinguish between symptomatic and disease-modifying effects of a treatment. Thus, in order for any novel, potential drug to demonstrate disease mod- ification there needs to be evidence that the drug, when adminis- tered for a period of time, stops disease progression. This can be demonstrated in a clinical trial by an absence of deterioration in clinical outcome measures by comparison with a control or placebo group. leicesershire schools between treatment groups are indeed evidence of disease modification rather than symptomatic effects (McGhee 2013). Changes in relevant biomarkers, such as presy- naptic striatal dopamine transporter (DAT) binding as assessed by [¹²³I]FP-CIT single photon emission CT (DaTSCAN) examina- tions, would provide additional evidence of disease modification. In addition, confounders may influence therapeutic effects. For example, while there is evidence that GLP-1 can cause weight loss (Vilsbøll 2012), it is known that the amount of levodopa and its maximum concentration in plasma are negatively correlated with body weight (Müller 2000), and consequently weight loss can lead to an increase in the effectiveness of levodopa. Thus an awareness of potential changes in weight loss due to GLP-1 and subsequent therapeutic effects on PD is essential in a study of GLP-1 receptor agonists.
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Emerging role of GLP-1 receptor agonists in the treatment of obesity

Emerging role of GLP-1 receptor agonists in the treatment of obesity

Abstract: The prevalence of obesity has increased dramatically in recent decades, both in the US and worldwide. Pharmacotherapy can augment the weight-reducing effects of lifestyle modification and can facilitate long-term weight maintenance. However, there is a paucity of pharmacologic agents approved for the treatment of obesity, and the use of existing weight loss medications is frequently limited by contraindications, drug interactions, adverse effects, limited coverage by third-party payers, and cost. In recent years, there has been an increased understanding and appreciation of the role of gastrointestinal hormones in the control of body weight. One such hormone, GLP-1, also plays an important role in glucose homeostasis. GLP-1 receptor agonists, such as exenatide and liraglutide, have been developed and are already approved for the treatment of type 2 diabetes. There has also been interest in the use of GLP-1 receptor agonists for the treatment of obesity in nondiabetic patients. This review explores the potential utility and limitations of exenatide and liraglutide as therapeutic agents for obesity.
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<p>Comparative Effectiveness of Long-Acting GLP-1 Receptor Agonists in Type 2 Diabetes: A Short Review on the Emerging Data</p>

<p>Comparative Effectiveness of Long-Acting GLP-1 Receptor Agonists in Type 2 Diabetes: A Short Review on the Emerging Data</p>

Abstract: Glucagon-like peptide-1 (GLP-1) receptor agonists have been available as glu- cose-lowering therapies for people with type 2 diabetes since 2006, when twice-daily exenatide was licenced. Since then, advances in peptide chemistry and delivery have allowed for once-daily and more recently once-weekly (QW) delivery of peptides in this class and there are currently three QW “ long-acting ” GLP-1 receptor agonists available in clinical practice. This short review describes the therapeutic landscape that is occupied by the modern type 2 diabetes glucose-lowering therapies with a particular focus on long-acting GLP-1 receptor agonists. The ef fi cacy and side-effect pro fi les of the available QW GLP-1 receptor agonists are discussed, focusing on head-to-head clinical trial comparisons. There is also an appraisal of the cardiovascular outcome trials, for which there has been an assess- ment of each of the QW GLP-1 receptor agonists, leading to clinical conclusions regarding their comparative effectiveness.
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Better cardiovascular outcomes of type 2 diabetic patients treated with GLP-1 receptor agonists versus DPP-4 inhibitors in clinical practice

Better cardiovascular outcomes of type 2 diabetic patients treated with GLP-1 receptor agonists versus DPP-4 inhibitors in clinical practice

We balanced GLP-1RA and DPP-4i initiators via pro- pensity score matching (PSM), using the nearest neigh- bor method and the logit distance, with maximum caliper set to 0.06% of the propensity score (PS) stand- ard deviation. The estimated PS were the output of a logistic regression model trained on patients’ charac- teristics, i.e., age at index date, sex, claims-based his- tory length (months between the first available claim and the index date), claims-based diabetes duration (months between the first diabetes-related claim and the index date); pre-existing conditions, i.e., hyperten- sion, dyslipidemia, peripheral circulatory complica- tions, myocardial infarction, ischemic heart disease, stroke or TIA, heart failure, cardiovascular disease, neurological complications, ocular complications, renal complications, chronic kidney disease, severe hypoglycemia, chronic pulmonary disease, systemic inflammatory disease, cancer, Charlson comorbid- ity index [22, 23]; glucose lowering medications in the
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The GLP 1 receptor agonists exenatide and liraglutide activate Glucose transport by an AMPK dependent mechanism

The GLP 1 receptor agonists exenatide and liraglutide activate Glucose transport by an AMPK dependent mechanism

Previous studies in rodent [14, 44] and human cell lines [16] have shown that GLP-1 and exendin-4 can stimulate glucose uptake. In L6 myotubes, exendin-4 augments insulin-stimulated glucose uptake via a molecular pathway that requires PI3  K activation [14]. However, whether or not exendin-4 might also exert a direct stimulating effect on glucose uptake was never addressed in muscle cells. In order to address this ques- tion, we studied the effect of the exendin-4 analog EXE, given alone and in combination with insulin, on the uptake of glucose by L6 myotubes. We also explored the molecular mechanisms involved in EXE-induced glucose uptake. Our data demonstrate that EXE induces glucose uptake by utilizing a molecular pathway different from the insulin stimulated PI3K/Akt/AS160 signaling cas- cade. Indeed, we show that EXE has the capability to increase glucose uptake in muscle cells in the absence of insulin, and interestingly, to an extent comparable to insulin. By using CC, which is a potent chemical inhibi- tor of AMPK and a number of other protein kinases [45], as well as a specific siRNA-mediated knockdown designed to reduce the protein expression of the α1 and α2 subunits of AMPK, we provide direct evidence that the stimulatory effect of EXE on glucose uptake is medi- ated by: (i) AMPK activation; (ii) activation of the Rab GTPase-activating protein TBC1D1, a paralog of AS160, highly expressed in skeletal muscle [17, 21]; and (iii) translocation to the plasma membrane of the insulin- dependent glucose transporter Glut-4 [15, 22].
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The effect of glucagon like peptide 1 (GLP 1) receptor agonists on cell viability, ADAM10 maturation and the proteolysis of ADAM10 substrates in SH SY5Y cells

The effect of glucagon like peptide 1 (GLP 1) receptor agonists on cell viability, ADAM10 maturation and the proteolysis of ADAM10 substrates in SH SY5Y cells

The combination of treatment with exendin-4 and TG showed a significant decline in the expression of NLGN-1 in comparison to TG alone (Fig. 3.3.6). Additionally, the combination of treatment with both the stressor and the drug displayed a significant increase in the shedding of NLGN-1 in comparison to the stressor alone (Fig. 3.3.7). Consequently, the reduction of NLGN-1 after treatment with exendin-4 and TG is accounted for by a significant increase in the shedding of NLGN-1 N-terminal following the same treatment. This indicates that exendin-4 is able to cleave this protein in response to stress, however previous data discussed in this study (section 4.3) implies that this mechanism does not involve the maturation of ADAM-10. Interestingly, Peixoto et al. reported that the proteolytic activity of matrix metalloprotease 9 (MMP9) is involved in the cleavage of NLGN-1 (Peixoto et al., 2012), which could be a possible component in the mechanism enforced by exendin- 4. The authors also described that the Ca 2+ /calmodulin-dependent protein kinase also plays a role in the cleavage of this protein, which is particularly interesting considering the apparent calcium homeostasis restorative effect of exendin-4 reported by studies mentioned in previous sections (4.2.2 and 4.4).
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Evaluating preferences for profiles of GLP-1 receptor agonists among injection-na&iuml;ve type 2 diabetes patients in the UK

Evaluating preferences for profiles of GLP-1 receptor agonists among injection-na&iuml;ve type 2 diabetes patients in the UK

Objective: To use a discrete choice experiment (DCE) to evaluate preferences for the actual treatment features and overall profiles of two injectable glucagon-like peptide-1 receptor agonists (dulaglutide and liraglutide) among patients with type 2 diabetes mellitus (T2DM) in the UK. Methods: In-person interviews were conducted in the UK to administer a DCE to patients with self-reported T2DM, naïve to treatment with injectable medications. The DCE examined six attributes of T2DM treatment each described by two levels: “dosing frequency,” “hemoglobin A1c change,” “weight change,” “type of delivery system,” “frequency of nausea,” and “frequency of hypoglycemia.” Part-worth utilities were estimated using random effects logit models and were used to calculate relative importance (RI) values for each attribute. A chi-square test was used to determine differences in preferences for dulaglutide versus liraglutide profiles. Results: A total of 243 participants [mean age: 60.5 (standard deviation 10.9) years; 76.1% male; mean body mass index: 29.8 (standard deviation 5.4) kg/m 2 ] completed the study. RI values
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SGLT2 inhibitors or GLP-1 receptor agonists as second-line therapy in type 2 diabetes: patient selection and perspectives

SGLT2 inhibitors or GLP-1 receptor agonists as second-line therapy in type 2 diabetes: patient selection and perspectives

Differences also exist within drug classes. Exenatide and liraglutide have slightly better weight and efficacy out- comes compared to other GLP-1RA. Once-daily or weekly formulations may be preferred by patients and improve adherence. Longer acting agents also tend to have greater effect on fasting blood glucose, whereas shorter acting agents target postprandial glucose. Amongst SGLT2-I, cana- gliflozin specifically has raised concerns about risk of bone fracture, although it is unclear whether an association exists with other SGLT2-I. Empagliflozin appears to reduce CV risk in patients with known ASCVD, although it has more modest improvements in glycemic control when compared to other SGLT2-I. Further data are needed to understand if the reduction in CV outcomes with empagliflozin is a class effect.
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Cardiovascular effects of Glucagon-like peptide 1 (GLP-1) receptor agonists

Cardiovascular effects of Glucagon-like peptide 1 (GLP-1) receptor agonists

The first pieces of evidence of the potential clinical benefit of GLP-1 agonists have emerged recently, point- ing to a decrease of major adverse cardiovascular and cerebrovascular events (MACCE) including stroke, MI, cardiac mortality, acute coronary syndrome, and revas- cularization procedures. A retrospective medical database analysis of T2D patients (n = 39,275) treated with exena- tide or other glucose-lowering therapies (n = 381,218) in- dicated that the GLP-1 agonist might reduce in 19% the incidence of MACCE and in 12% cardiovascular hospitali- zations [71]. Despite the absence of adverse cardiovascular effects has been confirmed, this benefit was not verified in an integrated analysis of 12 controlled, randomized, short- term clinical trials (12-52 weeks) comparing exenatide with placebo or insulin [72].
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Role and development of GLP-1 receptor agonists in the management of diabetes

Role and development of GLP-1 receptor agonists in the management of diabetes

Figure 1 Structures of native GLP-1, exenatide, and liraglutide. The N-terminal dipeptide “HA” (in green letters) of GLP-1 and liraglutide is the proteolytic cleavage site for DPP 4. red letters indicate changes introduced in derivatives or occur naturally in exendin-4 (and replicated in the synthetic version, exenatide). A crossed-out green arrow indicates absent DPP 4 activity, and a dotted green arrow indicates reduced DPP 4 activity. Exenatide long-acting release (LAr) is formulated with exenatide and poly( d , l lactic-co-glycolic acid) microspheres (yellow circles), biodegradable medical polymers commonly used in extended drug release formulation.
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Novel skeletal effects of glucagon-like peptide-1 (GLP-1) receptor agonists

Novel skeletal effects of glucagon-like peptide-1 (GLP-1) receptor agonists

To address this issue, a few studies were conducted examining if sclerostin production by osteocytes is modified in bone of diabetic rodents or in vitro when osteocytes are cultured in high glucose levels. Inconsistencies were observed [39, 70] and in vitro studies are however constrained by the fact that only osteocyte cell lines can be used and they are discrepancies regarding their production of sclerostin [39, 70]. Our recent study shows that the impaired bone microarchitecture and cellular turnover associated with T2DM-like conditions in diabetic ZDF rats are not correlated with changes in serum sclerostin levels, bone sclerostin expression or osteocyte viability [39]. On the other hand, high fat diet in mice resulted in increased serum sclerostin and dramatic alterations of osteocyte network organisation [71]. Few studies have investigated if GLP-1RAs could affect sclerostin production. Although most data agrees that GLP-1r is mainly expressed in immature osteoblasts, GLP-1r can be present in osteocytes where it co-localise with sclerostin [38], suggesting that GLP-1RAs may affect sclerostin production by osteocytes. Kim et al have indeed shown that sclerostin levels are increased in diabetes and can be down-regulated by exenatide treatment [38]. More recently, they demonstrate that the DPP-4 inhibitor vildagliptin lowers the increases levels of sclerostin induced by thiazolidinedione [72]. Our own results are more conflicting as we showed that exenatide but not liraglutide decreased sclerostin levels in OVX mice [31], but in contrast, sclerostin levels were increased with exenatide in diabetic mice while unchanged in IR rats (Pereira M, Gohin S, Roux JP, Cleasby ME, Mabilleau G, Chenu C, manuscript in revision). This may reflect differences in the currently available commercial assays for the measurement of sclerostin or the animal model making presently the measurement of serum sclerostin not very useful as a predictive biomarker for impaired bone formation in T2DM.
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Patient preferences in Italy: health state utilities associated with attributes of weekly injection devices for treatment of type 2 diabetes

Patient preferences in Italy: health state utilities associated with attributes of weekly injection devices for treatment of type 2 diabetes

weekly GLP-1 receptor agonists differ in terms of injection treatment process attributes. Therefore, this study focused on preferences and utility differences associated with three treatment-related attributes that vary among these treat- ments: 1) requirements for reconstitution (ie, mixing the medication) prior to injection, 2) waiting time required prior to the injection, and 3) whether patients are required to handle the injection needle. The first two attributes were hypothesized to be important to patients who prioritize ease of administration, while the third attribute is considered to be an important safety issue. 18,19 The UK study found that
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Pathogenesis and management of postprandial hyperglycemia: role of incretin-based therapies

Pathogenesis and management of postprandial hyperglycemia: role of incretin-based therapies

Mechanistic and clinical data for the GLP-1 receptor agonists and DPP-4 inhibitors in reducing PPG are discussed herein, with recent clinical trial results summarized in Tables 1–4. Regarding the clinical trial data, searches of the US National Library of Medicine PubMed.gov database were conducted in October 2012 for each of the various agents (approved and investigational), focusing on English-language reports of randomized controlled trials published since 2008 as monotherapy (placebo-controlled trials only) or as add-on therapy to metformin, a sulfonylurea, or insulin therapy (placebo-controlled or active-controlled; of note, trials evaluating their use as initial combination therapy, rather than add-on therapy, are not covered here). The full text of identified articles was reviewed to identify those that reported on PPG outcomes (Tables 1–4). Selected data available in meeting abstract form were also considered.
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Estimating the real world daily usage and cost for exenatide twice daily and liraglutide in Germany, the Netherlands, and the UK based on volumes dispensed by pharmacies

Estimating the real world daily usage and cost for exenatide twice daily and liraglutide in Germany, the Netherlands, and the UK based on volumes dispensed by pharmacies

This study adds to the literature on type 2 diabetes and GLP-1 receptor agonists by estimating the daily usage and costs of treatment with exenatide twice daily and liraglutide in the real world setting. Despite country-specific differ- ences in databases, prescribing and dispensing practices, the assumptions made, and the limitations of the methodology used, this study demonstrates that real world estimates of average daily dispensed doses of GLP-1 receptor agonist inhibitors derived from pharmacy data correspond reason- ably well to the dosages recommended by the summaries of product characteristics, given the titration schedule for each product. The only exception was the estimated mean daily usage of exenatide twice daily in the UK, which exceeded the recommended maximum dose by 0.49 µ g; this result could have been affected by the inability to analyze outli- ers, as only the average monthly data were available in the UK. In all three countries, the mean daily cost of exenatide twice daily was lower than that of liraglutide. Based on these
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Two novel dual GLP 1/GIP receptor agonists are neuroprotective in the MPTP mouse model of Parkinson's disease

Two novel dual GLP 1/GIP receptor agonists are neuroprotective in the MPTP mouse model of Parkinson's disease

desensitized in the brains of patients with PD (Aviles-Olmos et al., 2013b; Moroo et al., 1994; Morris et al., 2011). Analogues of incretin hormones have been developed to treat type II diabetes (Campbell and Drucker, 2013; Holst, 2004). The incretin hormones are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) (Baggio and Drucker, 2007; Campbell and Drucker, 2013; Doyle and Egan, 2003). Protease- resistant analogues of GLP-1 and GIP have shown neuroprotective effects in animal models of Alzheimer’s disease (Bomfim et al., 2012; Duffy and Holscher, 2013; Faivre and Holscher, 2013a, b; Li et al., 2010; McClean et al., 2011) and re-sensitize insulin signaling in the brain (Long-Smith et al., 2013; Shi et al., 2017). Furthermore, previous studies found that GLP-1 receptor agonists also have neuroprotective effects in animal models of PD (Bertilsson et al., 2008; Harkavyi et al., 2008; Li et al., 2009; Liu et al., 2015a; Zhang et al., 2015). The GLP-1 mimetic exendin-4 showed impressive effects in a pilot clinical study and in a phase II double blind, placebo controlled study in PD patients (Athauda et al., 2017; Aviles-Olmos et al., 2013a; Aviles-Olmos et al., 2014). We have shown that GLP-1 and also GIP analogues are
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