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Non-glycaemic effects mediated via GLP-1 receptor agonists and the potential for exploiting these for therapeutic benefit: focus on liraglutide
Article first published online: 8 MAR 2012
© 2012 Blackwell Publishing Ltd
Diabetes, Obesity and Metabolism
Special Issue: Liraglutide in the Treatment of Type 2 Diabetes: Summary of Phase 3 Clinical Data, Practical Considerations and Non-glycaemic Effects. Guest Editor: Alan J. Garber
Volume 14, Issue Supplement s2, pages 41–49, April 2012
How to Cite
Vilsbøll, T. and Garber, A. J. (2012), Non-glycaemic effects mediated via GLP-1 receptor agonists and the potential for exploiting these for therapeutic benefit: focus on liraglutide. Diabetes, Obesity and Metabolism, 14: 41–49. doi: 10.1111/j.1463-1326.2012.01579.x
- Issue published online: 8 MAR 2012
- Article first published online: 8 MAR 2012
- Date submitted 17 November 2011; date of final acceptance 11 January 2012
The glucagon-like peptide-1 receptor agonists (GLP-1 RAs) liraglutide and exenatide can improve glycaemic control by stimulating insulin release through pancreatic β-cells in a glucose-dependent manner. GLP-1 receptors are not restricted to the pancreas; therefore, GLP-1 RAs cause additional non-glycaemic effects. Preclinical and clinical trial data suggest a multitude of additional beneficial effects related to GLP-1 RA therapy, including improvements in β-cell function, systolic blood pressure and body weight. These effects are of a particular advantage to patients with type 2 diabetes, as most are affected by β-cell dysfunction, obesity and hypertension. Transient gastrointestinal adverse events, such as nausea and diarrhoea, are also common. To improve gastrointestinal tolerability, an incremental dosing approach is used with liraglutide and exenatide twice daily. A potential protective role for GLP-1 RAs in the cardiovascular and central nervous systems has been suggested from animal studies and short-term clinical trials. These effects and other safety aspects of GLP-1 therapy are currently being investigated in ongoing long-term clinical studies.
Considerable interest surrounds the therapeutic potential of incretin hormones for the treatment of type 2 diabetes (T2D). Much of this has focused on glucagon-like peptide-1 (GLP-1) in particular. Following secretion from gastrointestinal L-cells, GLP-1 binds its receptor on pancreatic β-cells to stimulate insulin release and synthesis (and inhibit glucagon) in a glucose-dependent manner .
Many patients with T2D show an impaired incretin response following meals , attributable to resistance to the glucose-dependent insulinotropic peptide (GIP) that cannot be compensated for by endogenous GLP-1 . Pharmacological levels of GLP-1, achieved through continuous GLP-1 infusion, have been shown to normalise fasting blood glucose levels ; however, the therapeutic potential of native GLP-1 is limited because of its short (1–2 min) half-life following rapid degradation by dipeptidyl peptidase-4 (DPP-4) . To overcome this short half-life, two classes of incretin therapies have been developed: DPP-4 inhibitors, which raise endogenous levels of plasma GLP-1 and GIP (e.g. sitagliptin, vildagliptin, alogliptin, saxagliptin and linagliptin), and DPP-4-resistant GLP-1 receptor agonists (GLP-1 RAs; liraglutide once daily, exenatide twice daily and exenatide once weekly).
Both liraglutide and exenatide share amino acid sequence identity to native human GLP-1 (97 and 53%, respectively). The structural modifications of these synthetic GLP-1 RAs ensure a prolonged period of action in vivo. For example, the addition of a C16 fatty acid to Lys26 in liraglutide allows the molecule to reversibly bind to albumin in the bloodstream and enables self-association at injection sites , both of which result in a prolonged half-life that allows once-daily dosing.
In phase 3 clinical trials, improvements in glycaemic control occurred in patients with type 2 diabetes treated with agents from both of these classes of incretin-based therapies [6–18]; however, efficacy is more pronounced with GLP-1 RAs, which provide the additional benefit of promoting weight loss .
Because of the widespread localisation of GLP-1 RAs across many tissues, additional systemic effects (both positive and negative) accompany the use of incretin therapies. Whilst the majority of these effects are beneficial, such as those reported for the cardiovascular system, the kidneys, the gastrointestinal system and the central nervous system (CNS), adverse events related to the gastrointestinal system are also relatively common, particularly early in therapy. In support of these extra-pancreatic effects, clinical trials with GLP-1 RAs have shown potential improvements in body weight , systolic blood pressure (SBP) and β-cell function [9,10,12,14,16,17]. As progressive β-cell dysfunction is an underlying factor in the development of T2D, and excess weight and hypertension are common among patients with the condition [21,22], treatment with GLP-1 RAs seems to have the potential to offer non-glycaemic benefits not currently provided by other antidiabetic therapies, which typically only improve blood glucose. This article will review the non-glycaemic effects of native GLP-1 and GLP-1 RAs from preclinical and clinical trials, with emphasis on liraglutide. The glycaemic effects of liraglutide in clinical trials are described in accompanying articles within this supplement [23,24].
GLP-1 and GLP-1 RAs Improve β-cell Function
Declining β-cell function is one of the hallmarks of T2D. Inadequate glycaemic control typically results in progressive pancreatic β-cell failure; thus, antidiabetic treatment generally requires intensification as the disease progresses . Both animal and in vitro studies have shown potential benefits of GLP-1 exposure on β-cell mass by using a combination of increased β-cell neogenesis and proliferation, as well as reduced apoptosis [26,27].
In vitro studies examining the effect of GLP-1 on cultured rat pancreatic ductal cells (ARIP cells) revealed that GLP-1 exposure lowered the proportion of cells in S phase (after 12 hours, 9% of cells exposed to GLP-1 were in S phase compared with 16% of cells exposed to vehicle alone; p < 0.05), whilst a parallel increase in the number of cells in G1 phase was also observed (after 12 hours, 84% of cells exposed to GLP-1 were in G1 phase compared with 68% of cells cultured in a serum-free medium; p < 0.01) . These changes are symptomatic of a slowdown of cellular growth, which can promote cellular differentiation in the presence of additional factors. Incubation with GLP-1 also promoted expression of β-cell-specific genes (including insulin) and a reduction in levels of CK-20 (a marker of ductal epithelial cells), indicating that GLP-1 promoted the differentiation of pancreatic ductal cells to β-cells. In support of this, cells cultured in the presence of GLP-1 were able to secrete insulin in a glucose-dependent manner, whilst control cells (exposed to the vehicle only) were unable to secrete insulin.
Zucker diabetic fatty rats (ZDF) exhibited improved glycaemic control following a 2-day continuous infusion of GLP-1 . Ex vivo immunostaining of the pancreas revealed that this improved glycaemic control correlated with increased levels of Ki-67, a marker of β-cell proliferation, in the endocrine and exocrine components. Furthermore, markers of apoptosis (caspase-3 expression, TUNEL staining) were diminished and a marked reduction of fragmented nuclei was observed in islet cells. These data indicated that GLP-1 infusion promoted proliferation and prevented apoptosis of pancreatic β-cells in ZDF rats.
GLP-1 RAs also have a beneficial effect on β-cell function, as shown in animal studies [28–31]. β-cell mass was significantly increased following liraglutide treatment in hyperglycaemic animals (20.9 ± 2.6 mg vs. 12.4 ± 1.8 mg in vehicle-treated ZDF rats) . By contrast, liraglutide had little or no effect in normoglycaemic animals. Similar positive effects on β-cell mass were seen with exendin-4 (a GLP-1 RA), with increases in β-cell mass of up to 40% in treated rats .
In a 6-week trial, patients with T2D receiving a continuous infusion of native GLP-1 exhibited increased fasting C-peptide concentrations [mean (s.e.): week 0: 955  pmol/l; week 6: 1136  pmol/l], indicative of improved β-cell function . In a single-dose placebo-controlled crossover study, liraglutide was associated with restoration of β-cell responsiveness to physiological hyperglycaemia in 10 subjects with T2D . Furthermore, in phase 3 studies, pancreatic β-cell function indices were improved following liraglutide treatment [1.8 mg liraglutide daily, homeostatic model assessment (HOMA)-β increase: 27–35%; decrease in proinsulin:insulin ratio of 0–0.12] [9–12,14]. Clinical trials evaluating the efficacy of twice-daily exenatide revealed similar improvements in β-cell function (proinsulin:insulin ratio decreased by approximately 0.15) [16,17]. Exenatide over 52 weeks also led to a 2.46-fold (p < 0.0001) increase in combined glucose- and arginine-stimulated C-peptide secretion, assessed using an arginine-stimulated hyperglycaemic clamp, compared to insulin glargine . These measures returned to pretreatment values in both groups 4 weeks after treatment cessation. Following 3 years of treatment in an extension study, however, a disposition index, first-phase glucose stimulated C-peptide secretion adjusted for insulin sensitivity value, remained higher in the exenatide-treated group compared to the glargine-treated group (p = 0.028), suggesting a possible sustained improvement in β-cell health . Together, these data suggest that early use of GLP-1-based therapies may have the ability to limit the pancreatic β-cell damage associated with T2D, thus potentially delaying the requirement for insulin therapy.
GLP-1, GLP-1 RAs and Cardiovascular Risk
Patients with T2D frequently present with hyperglycaemia, hypertension, obesity and dyslipidaemia, all of which are risk factors for cardiovascular disease [36,37]. By reducing the occurrence of these risk factors, the incidence of cardiovascular disease in this population could be reduced .
Expression of GLP-1 RAs has been shown in coronary arterial endothelial cells ; however, in vitro studies revealing a dose-dependent vasorelaxant effect of GLP-1 on rat femoral artery rings mediated by GLP-1 receptor binding also showed that the effect remained intact after the mechanical removal of the endothelium . In patients with T2D and stable coronary heart disease, GLP-1 infusion significantly increased relative changes in brachial artery diameter, measured by flow-mediated vasodilation (FMD) response from baseline (3.1 ± 0.6% vs. 6.6 ± 1.0%; p < 0.05), indicating a potential cardioprotective role for native GLP-1 . Patients with acute myocardial infarction and angioplasty who received a 72-h infusion of GLP-1 experienced improved cardiac function that reduced in-hospital mortality rate and the duration of hospitalisation . Furthermore, heart failure patients receiving GLP-1 infusion (5-week duration, added to standard therapy) had significantly improved left ventricular ejection fraction and myocardial oxygen uptake compared to patients receiving standard therapy alone .
GLP-1 RAs have also been proposed to play a cardioprotective role. Treatment with liraglutide has been reported to protect against myocardial infarction in mice . Pretreatment with liraglutide resulted in decreased perioperative mortality (28 days after ligation, perioperative mortality was 20% in mice pretreated with liraglutide vs. 77% of mice pretreated with phosphate buffered saline (PBS); p = 0.0001), fewer cardiac rupture events and a significant reduction in infarct expansion (total left ventricular circumference: 20.9 ± 1.7% vs. 28.8 ± 3.3% in mice treated with PBS; p = 0.02 ) following the induction of myocardial infarction. Furthermore, levels of biomarkers of heart failure and myocardial apoptosis were reduced in liraglutide-treated mice. Cardioprotective effects have also been observed in exenatide/exendin-4-treated animals [44,45]. For example, exendin-4 (0.3 nM) was shown to produce a strong infarct-limiting action (from 33.2 ± 2.7% to 14.5 ± 2.2% of the ischaemic area; p < 0.05) and augment left-ventricular performance during reperfusion of isolated rat hearts . Exenatide was also found to increase myocardial salvage compared to placebo (p = 0.003 ) in patients with ST-segment elevation myocardial infarction when administered intravenously from 15 min before through 6 h after primary percutaneous coronary intervention .
In phase 3 studies, patients with T2D treated with liraglutide also exhibited reduced lipid levels [e.g. low-density lipoprotein (LDL) cholesterol, −0.20 mmol/l] and levels of cardiovascular risk biomarkers including plasminogen activator inhibitor-1 (PAI-1), brain natriuretic peptide (BNP) and high sensitivity C-reactive protein (hsCRP) (−7.6%, −11.9% and −23.1%, respectively) [47,48] (figure 1). Elevated levels of PAI-1 have previously been implicated in endothelial cell dysfunction . Twice-daily exenatide also reduced lipid levels and cardiovascular biomarker levels, but to a lesser degree than liraglutide (e.g. −0.15 mmol/l, −1.2%, −3.9% and −15.6% for LDL cholesterol, PAI-1, BNP and hsCRP, respectively) [47,48]. A recent meta-analysis of data from 10 randomised controlled trials (RCTs) reported that GLP-1 RA treatment resulted in a greater reduction in total cholesterol [weighted mean difference; WMD (95% CI): −0.1 (−0.16, −0.04) mmol/l] than comparator interventions [placebo, oral antidiabetic drugs (OADs) or insulin] .
In clinical trials, a 2–5.6 mmHg decrease in SBP from baseline to 26 weeks was seen in patients treated with 1.8 mg liraglutide compared with a 0.9–1.8 mmHg decrease in individuals treated with placebo [9,10,12–14]. Similar decreases in SBP were observed following twice-daily (1.3–3.4 mmHg) and once-weekly (2.5–7.9 mmHg) exenatide treatment [50–57]. A meta-analysis of data from GLP-1 RA randomised controlled trials reported that reductions in SBP and diastolic blood pressure (DBP) are greater with GLP-1 RAs than with comparator therapies [WMD (95% CI): −3.57 (−5.49, −1.66) mmHg and −1.38 (−2.02, −0.73) mmHg, respectively] . The causative mechanism behind the liraglutide- and exenatide-induced reductions in blood pressure is unclear; however, it has been speculated that, with liraglutide at least, this effect is due to increased natriuresis , as it occurs well before weight loss .
Taken together, these data indicate that GLP-1-based therapies can have beneficial effects on a range of cardiovascular risk factors. These effects may be mediated through GLP-1 RA expression in cardiac tissues, and could occur independently of weight loss. To date, these findings have been limited to preclinical models and relatively short clinical trials, thus validation in longer clinical studies is now required.
Effect of GLP-1 and GLP-1 RAs on the Kidneys
The GLP-1 receptor is also expressed in the kidneys , where GLP-1 is reported to regulate water and salt homeostasis . Excess sodium reabsorption at the proximal renal tubes is a common feature of type 2 diabetes and obesity [58,62]; the resulting extracellular volume expansion can ultimately lead to hypertension in affected individuals .
Intravenous administration of native GLP-1 resulted in a profound dose-dependent increase in diuresis in rats; water intake, by contrast, was dose-dependently inhibited by GLP-1 . Similar effects occurred following administration of a single dose of liraglutide (200 µg/kg), with decreased overnight water intake and increased diuresis observed in both normal and obese rats . When treated continuously with liraglutide for 10 days, obese rats experienced an immediate significant reduction in water intake coupled with increased diuresis, leading to a negative water balance. Water intake normalised within a day of cessation of treatment, suggesting drug washout, with no lasting effect on water homeostasis . During this study, despite the increase in urinary water excretion, the levels of plasma sodium and potassium were unaffected.
In healthy human beings, GLP-1 infusion decreased renal sodium reabsorption following either an intravenous or an oral salt load . This decrease was associated with a corresponding increase in urinary pH. Obese subjects, when treated with GLP-1, exhibited a significantly greater increase in urinary sodium excretion compared with those individuals receiving a placebo . In addition, urinary H+ secretion was reduced in these subjects and a 6% decrease in glomerular filtration rate (GFR) was observed. GFR is often increased (through tubulo-glomerular feedback) in response to elevated sodium reabsorption; therefore the observed GFR reduction is likely correlated to the concurrent decrease in sodium retention. These data indicate that GLP-1 may act on the Na+/H+ exchange at the proximal renal tubule with the potential to increase sodium excretion, which in turn reduces volume expansion and glomerular hyperfiltration . Clinically, this may reduce the incidence of arterial hypertension and renal damage in patients with T2D.
Type 2 diabetes is the leading cause of renal impairment because of inadequate glycaemic control ; thus, studies that show the efficacy and safety of antidiabetic drugs in patients with renal impairment are of interest. Combined data from five studies showed that the twice-daily exenatide formulation significantly reduced creatinine clearance by 36% in patients with moderate renal impairment and 84% in patients with end-stage renal disease receiving dialysis . Twice-daily exenatide is therefore not recommended for use in patients with severe renal impairment or end-stage renal disease, and caution is advised during treatment initiation in patients with moderate renal disease . A meta-analysis of data from the six Liraglutide Effect and Action in Diabetes (LEAD) trials revealed no significant difference in creatinine clearance between liraglutide-treated patients with mild renal impairment compared with the general study population . Furthermore, no significant treatment effects on HbA1c reductions and frequency of nausea were observed in patients with mild renal impairment. These data indicate that the efficacy and safety of liraglutide are not affected by mild renal impairment, and suggests that liraglutide has no negative effect on renal function. However, because of limited experience in patients with mild, moderate or severe renal impairment, US guidelines recommend that liraglutide should be used with caution in this population . In Europe, treatment with liraglutide is not currently recommended for use in patients with moderate or severe renal impairment . There is an ongoing study evaluating the efficacy and safety of liraglutide in severe kidney disease .
Effect of GLP-1 and GLP-1 RAs on the Gastrointestinal System
At the time of diagnosis, many individuals with T2D are overweight or obese ; thus the additional weight gain seen with many antidiabetic treatments can be of serious concern. The use of incretin-based therapies, with their potential to be weight neutral (DPP-4 inhibitors) or promote weight loss (GLP-1 RAs), could therefore be particularly beneficial for the treatment of T2D. The mechanism through which GLP-1 influences food intake (and thus weight) is not completely understood, although GLP-1 receptor expression has been shown in several brain locations that control appetite and satiety, suggestive of a central mechanism [72–75].
Food Intake. A potential role for GLP-1 in appetite suppression has been shown in animal models [64,76]. In Wistar rats, intravenous GLP-1 administration decreased food intake in a dose-dependent manner at both 30 and 60 min after the onset of feeding . This effect of native GLP-1 was abolished by the prior administration of exendin(9-39) amide, a GLP-1 RA. Subsequent experiments in this study revealed that a single injection of liraglutide (200 µg/kg) reduced food intake in a comparable manner in both normal and obese rats (normal rats: control: 22.4 ± 0.7 g vs. liraglutide: 8.7 ± 1.3 g of food; obese rats: control: 12.5 ± 1.9 g vs. liraglutide: 5.8 ± 0.7 g of food; p < 0.05). Similar results were observed in obese minipigs, with reduced food intake observed after 3 weeks of once-daily liraglutide (7 µg/kg) treatment (mean daily food intake during treatment period: 7.3 ± 0.3 MJ vs. 18.4 ± 0.6 MJ during the pretreatment period and 19.2 ± 0.5 MJ during the post-treatment period; p < 0.001) . This effect on reduced energy intake was maintained for the remaining 4 weeks of the study; however, following the cessation of liraglutide treatment, food intake arose to pretreatment levels.
In addition to reduced calorie intake, liraglutide treatment has been associated with a shift in food preference . In obese candy-fed rats, twice-daily liraglutide treatment shifted food preference from candy to chow, suggestive of reduced cravings for simple carbohydrate and fat, which could aid the weight loss seen in these animals (mean body weight at study initiation: 315 ± 11 and 317 ± 7 g for liraglutide-treated and control rats, respectively; mean body weight at end of study: 301 ± 10 vs. 344 ± 8 g for the liraglutide-treated and control rats, respectively; p < 0.001 between treatment groups). GLP-1 infusion was also seen to reduce energy intake in human beings; a mean reduction of 11.7% was seen in individuals receiving liraglutide compared with individuals receiving a placebo .
The decreased food intake observed in rats and obese minipigs could also be because of the delay in gastric emptying observed following liraglutide treatment [79,80]. In obese minipigs, gastric emptying was not affected by the induction of diabetes (through either nicotinamide, or nicotinamide and streptozotocin treatment), but a reduction in gastric emptying was seen following treatment of the diabetic minipigs with liraglutide  (figure 2). However, a recent study questioned the involvement of liraglutide- and exenatide-induced gastric emptying in the weight-lowering effect of these agents . In rats, the effect of liraglutide on gastric emptying seemed to disappear by day 14, despite continuous treatment (vehicle: 9362 ± 469 µg/ml × min; liraglutide: 8135 ± 380 µg/ml × min); conversely, a profound reduction in gastric emptying was still evident with exenatide at the same time-point (591 ± 137 µg/ml × min). As both agents resulted in similar steady decreases in weight during the study period (liraglutide: 318 ± 5 g; exenatide: 303 ± 8 g), it was suggested that the effects of liraglutide on the appetite signals in the brain, such as hindbrain GLP-1 receptor activation , and not gastric emptying, could be the main mechanism for the observed weight loss with this agent. A study in male diet-induced obese rats found that reduced food intake and body weight in response to liraglutide were accompanied by mRNA changes in the hypothalamus . Other studies have found that, although liraglutide decreases the activation of food-regulating brainstem GLP-1 neurons by food, it does not appear to lower food intake via this system, and GLP-1 receptors located in more central areas may be involved in liraglutide-induced weight loss [82,83].
Weight Loss. The liraglutide-induced reduction in food intake observed in obese minipigs was associated with significant weight loss, with an average of 4.3 ± 1.2 kg (4–5% body weight) lost during the treatment period (p < 0.05) . This effect was not sustained following the cessation of treatment: during the 7-week post-treatment period, the mean body weight increased by 7 kg. Weight loss has also been shown in candy-fed rats receiving liraglutide , and also in animal studies involving exenatide .
After 6 weeks' infusion with either GLP-1 or saline, patients with T2D who were receiving GLP-1 had a greater percentage weight loss at study end than patients receiving saline  (figure 3). Positive effects on body weight have since been shown in numerous clinical trials with the GLP-1 RAs liraglutide and twice-daily exenatide. With twice-daily exenatide in combination with metformin, for example, a weight loss of 3.6 kg was apparent after 1 year ; after 3 years, in combination with metformin and/or sulphonylureas (SUs), the weight loss was 3.9 kg . Weight loss observed with exenatide once weekly ranged from 2.0 to 3.7 kg in phase 3 studies [52–57]. For liraglutide, treatment with the 1.8 mg dose resulted in up to 3 kg weight loss from baseline after 26 weeks; weight change with placebo varied from a weight loss of 1.5 kg to a 0.6 kg weight gain over that time [9,10,12–14]. The lowest weight loss was observed when liraglutide was combined with an SU , possibly due to SU-associated weight gain and/or withdrawal of metformin. A longer-term combination (metformin) study showed weight loss with liraglutide 1.8 mg of 3.7 kg at 1 year . Liraglutide-induced weight loss in human beings may be attributed to feelings of satiety and fullness  that results in a decreased energy intake . In a substudy involving patients from the LEAD-2 and LEAD-3 studies, weight loss was found to correspond to a reduction in visceral and subcutaneous fat (as opposed to lean tissue mass), thus reducing the long-term risk of cardiovascular disease . Weight loss with liraglutide is also discussed elsewhere within this supplement [23,24].
The majority of GLP-1 RA-associated side effects are gastrointestinal, with most complaints relating to nausea, particularly early in treatment. Clinical data have revealed that the effect of liraglutide treatment on weight loss, which is generally a more long-term effect than the nausea, was observed irrespective of gastrointestinal adverse effects . The gastrointestinal side effects of liraglutide are discussed in more detail in an accompanying article in this supplement .
A Potential Neuroprotective Role for GLP-1
The incidence of Alzheimer's disease, Parkinson's disease and stroke is increased in T2D patients [92–94], suggesting common pathways of neuronal cell death that may be related to insulin dysregulation. Insulin receptor desensitisation, similar to that seen in T2D, has been observed in the brain of Alzheimer's patients, resulting in the coining of the term ‘type 3 diabetes' . The desensitisation exposes neurons to toxic influences with the potential to lead to neurodegeneration. However, GLP-1 receptor activation has been reported to reverse neuronal insulin receptor desensitisation , and as exendin(9-39)  and liraglutide  are both capable of crossing the blood-brain barrier, GLP-1 RAs may provide protection against neurodegeneration via this mechanism.
GLP-1 RAs have also been shown to significantly affect synaptic plasticity in mice . Liraglutide and other novel protease-resistant GLP-1 agonists (Asp7GLP-1, N-glyc-GLP-1 and Pro9GLP-1) provided a rapid facilitatory effect on long-term potentiation (LTP), whereas exendin(9-39) amide impaired LTP. Additionally, GLP-1 and exendin-4 administration provides complete protection from glutamate-induced apoptosis in cultured rat hippocampal cells . Perry et al. later showed that GLP-1 can protect against oxidative stress and alter β-amyloid precursor protein (βAPP) processing . In vivo, GLP-1 infusion reduced amyloid β (Aβ) levels in the brains of mice; Aβ is produced following cleavage of βAPP, and is believed to play a role in the pathogenesis of Alzheimer's disease. These results clearly show that GLP-1 and GLP-1 RAs elicit effects on neurotransmission in the brain; however, it remains to be proven whether these effects translate to clinical benefits for Alzheimer's disease patients receiving GLP-1-based therapies for concurrent T2D.
To date, no study has described the course of a co-existent neurological condition whilst undergoing GLP-1 RA therapy. Data from additional large long-term studies are expected to emerge in the near future; these may include such co-morbid individuals and provide evidence for or against a neuroprotective role for GLP-1-based therapies in human beings.
As a result of widespread action of endogenous GLP-1 on various tissues and organs, GLP-1 RAs such as liraglutide and exenatide would be expected to exert multiple effects, potentially both beneficial and adverse, throughout the body. Preclinical and clinical data suggest that in addition to improved glycaemic control, treatment with GLP-1 RAs offers additional benefits to patients with T2D, including weight loss, reduced SBP and improved β-cell function. At present, the main adverse effects of GLP-1 and GLP-1 RAs appear to be transient gastrointestinal events.
A protective role for GLP-1 RAs in the cardiovascular system has also been suggested in preclinical studies, raising the possibility that GLP-1 RAs may lower the risk of cardiovascular events in patients with T2D. Control of cardiovascular risk factors is particularly important in this patient population, and the US Food & Drug Administration consequently requires that the manufacturers of T2D medications perform long-term clinical safety studies in patients who are at a high risk of developing cardiovascular disease .
In summary, in addition to improved glycaemic control, GLP-1 RAs appear to provide a multitude of other beneficial effects for patients with T2D. Data from long-term clinical studies that could support these findings and report on their sustainability are now eagerly awaited.
The assistance of Watermeadow Medical, New York, NY, USA, funded by Novo Nordisk Inc, Princeton, NJ, USA, in preparing this article is gratefully acknowledged.
Conflict of Interest
Prof Vilsbøll has been a consultant for Merck Sharp & Dohme and Novo Nordisk, and has participated in speakers' bureaus on behalf of AstraZeneca, Bristol-Myers Squibb, and Eli Lilly. Dr Garber has been a consultant/advisory board member for Boehringer Ingelheim, Daiichi Sankyo, LipoScience, Merck, Novo Nordisk and Takeda, and has participated in speakers' bureaus on behalf of Daiichi Sankyo, Merck, Novo Nordisk and Santarus. He is currently a member of the Board of Directors of the American Association of Clinical Endocrinologists. Prof Vilsbøll and Dr Garber both wrote and amended the manuscript comprehensively prior to submission.
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