The Use of Exenatide in Managing Markers of Cardiovascular Risk in Patients with Type 2 Diabetes: A Systematic Review

Objective: This review examines the use of exenatide twice daily in managing changes in markers of cardiovascular risk in patients with type 2 diabetes. Background: Type 2 diabetes is a progressive metabolic disorder, which results from defects in insulin secretion and/or insulin action leading to chronic hyperglycaemia and associated cardiovascular complications. Despite the use of diet, exercise, oral antihyperglycaemic agents and insulin, the progressive nature of the condition means that the levels of the preventive and treatment measures would have to be increased and/or new therapies have to be developed in order to address the long term impact of type 2 diabetes. The advent of exenatide, a glucagon-like peptide-1 receptor agonist provides a useful basis for managing type 2 diabetes and related cardiovascular complications without the side effects of regular diabetes therapies. However, exenatide twice daily is often used in combination with other therapies, although the mechanism of exenatide in managing diabetes and and associated cardiovascular risks and complications remain complex and still evolving. Method: A range of databases including EBSCOhost online research database were used to access articles based on PICO (Population, Interventions, Comparative Interventions, Outcomes) framework and Boolean operators. Results: Eleven randomised controlled studies which met the inclusion criteria were selected for this review. Nine of the eleven studies showed significant decrease in body weight among participants in the exenatide group compared with placebo or control group while the other two studies did not report statistically significant differences in body weight. In adition, all the studies showed statistically significant decrease in glycated haemoglobin (HbA1c) in the exenatide group compared to controls except in one study. In the present review, the seven studies, which looked at the effect of exenatide twice daily on lipid profile, did not find any significant difference between the exenatide group and the control group except for High density lipoprotein-cholesterol in two of the studies. However, statistically significant decrease was observed between exenatide group and controls with respect to blood pressure (systolic and/or diastolic) in these studies. Discussion: It would appear that exenatide is more effective in reducing body weight in patients with type 2 diabetes when used in combination with metformin than when used alone or in combination with thiazolidinedione. The findings of this review would suggest that exenatide twice daily may be useful in managing cardiovascular risks and complications by reducing body weight, HbA1c and blood pressure.


Introduction
Type 2 diabetes is a progressive metabolic disorder of multiple aetiology resulting from defects in insulin secretion from the beta cells and/or insulin resistance in peripheral tissues leading to chronic hyperglycaemia [1].
Patients with type 2 diabetes are at greater risk of developing cardiovascular disease (CVD). According to Saraiva and Sposito [2], about 68% of people over 65 years of age with diabetes die of some form of cardiovascualr disease and CVD deaths amongst adults with diabetes are two to four times higher than those without diabetes. Although some observational studies have demonstrated that a higher glycated haemoglobin (HbA1c) level was associated with increased risks of cardiovascular diseases and deaths, the underlying mechanisms remain complex [3,4].
The progressive nature of type 2 diabetes despite the use of diet, physical activity and current therapies, such as metformin, sulfonylurea and insulin, may explain why therapeutic requirements tend to increase with time [1,5]. Therefore, other strategies have to be developed in order to control the resulting hyperglycaemia and associated complications although researchers continue to debate which combination therapies will be effective in controlling hyperglycamia [5]. For example, Jansson et al. [6] demonstrated the protective effect of low-cost diabetes drugs on the negative influences of hyperglycaemia regarding all cardiovascular diseases combined and myocardial infarction. The addition of sulfonylurea and thiazolidinedione as treatment for diabetes are useful alternatives, however, these may have their limitations including the problems of hypoglycaemia, their tendency to elicit weight gain and oedema with potential to reduce patient compliance [1,5]. Therefore, new therapies, which do not have the usual side effects of the current therapies, have to be developed.
The National Institute for Health and Care Excellence (NICE) guideline [7] in the UK clearly outlined the algorithm for blood glucose lowering therapy in adults with type 2 diabetes. According to the guideline, if a triple therapy (such as metformin, a Dipeptidyl peptidase-4-inhibitor and sulfonylurea) is not effective, not tolerated or contraindicated, then, it will be useful to consider combination therapy with metformin, a sulfonylurea and a Glucagon-like peptide-1 (GLP-1) mimetic for adults with type 2 diabetes. To qualify for this treatment, the patients should have body mass index (BMI) of ≥ 35 kg/m 2 or have a lower BMI than 35 kg/m 2 and for whom insulin therapy would have significant occupational implications, or weight loss would benefit other significant obesity related co-morbidities. Similar approach in the form of algorithm for the initiation and adjustment of therapy in the management of hyperglycaemia in patients with type 2 diabetes has been developed [8]. This framework is based on consensus between the American Diabetes Association and the European Association for the Study of Diabetes [8].
The advent of the use of GLP-1 based therapies has brought new dimension in the management of type 2 diabetes and associated cardiovascular complications. According to McCormack [9], human GLP-1 is produced by L-cells of the intestinal mucosa and is an incretin, a gastrointestinal hormone responsible for the enhanced secretion of insulin from the beta cells of the pancreas in response to food intake. In addition, GLP-1 receptor agonists, such as exenatide, significantly decrease glycated haemoglobin through suppressing glucagon production, delaying gastric emptying, and reducing appetite and food intake by increasing satiety [10].
Exenatide is a 39-amino acid peptide and is an incretin mimetic, which was the first of the new incretin mimetic class of antihyperglycaemic agents to be marketed in the US and European Union [9,11]. Exenatide is a short acting agent, which can be administered subcutaneously twice daily (exenatide BID) although the extended release formulation can be administered once weekly (exenatid QW) [9].
There is evidence that exenatide has some advantages over current therapies for patients with type 2 diabetes. It does decrease the risk of severe hypoglycaemia when used in the absence of insulin or sulfonylurea and it is associated with reductions in body weight in the absence of diet and exercise programme [11,12]. It has been reported that GLP-1 can stimulate the proliferation and neogenesis of beta cells and may also inhibit their apoptosis [13]. In addition, GLP-1 decreases gastrointestinal motility, which could extend the entry of nutrients to be absorbed by the gastrointestinal tract and thus controls postprandial glucose levels and ensure normal glucose homeostatis [2]. Impairment in the secretion of GLP-1 has been considered in the pathophysiology of type 2 diabetes and the administration of GLP-1 receptor agonists, which restores GLP-1 function has been shown to promote insulin secretion, sensitivity and enhance long term prognosis including reduction in cardiovascular risks and complications [14].
In patients with type 2 diabetes, the incretin effect is significantly impaired due to reduced production of GLP-1, metablolism and/or impairment of their actions [13]. The incretin effect has been defined as the difference in insulin secretion from an oral gluscose load compared with intravenous glucose administration and results from the observation that intrajejunal glucose enhances greater insulin release than intravenous glucose administration [2,15].
In view of the above, this is a systematic review of randomised controlled studies aimed at evaluating the potential role of exenatide and combination treatments on physiological and biochemical markers of cardiovascular risk in patients with type 2 diabetes. The objective of this review is to examine the use of exenatide twice daily in managing changes in markers of cardiovascular risk in patients with type 2 diabetes.

Methods
This review involved a literature search including a general scoping of the data bases which found previous reviews relevant to the population and intervention of interest, but these were either more than 5 years old, were narrative reviews or included other GLP-1 agonists, such as liraglutide, and/or included studies which were not randomised. The current systematic review is based only on randomised controlled studies.
The literature search strategy for this review relied on previously published guidelines for reviews [16,17] and was based on the PICO framework; P (Population-patients with type 2 diabetes), I (Interventions-exenatide twice daily), C (Comparative interventions-control group, placebo) and O (Outcomes-Glycaemic control, glycated haemoglobin, microvascular complications, macrovascular complications, cardiovascular complications). A number of databases including EBSCOhost online research database, encompassing Academic search premier, Medline, Psychology and Behavioural sciences collection, PsycINFO®, SPORTDiscuss and Cumulative Index to Nursing and Allied Health Literature (CINAHL) Plus were accessed.

Inclusion Criteria
Studies included were those written in English and published between 2010 and 2016 only. In addition, only randomised controlled studies were selected for review.

Exclusion Criteria
Studies which did not meet the inclusion criteria outlined above were excluded from the review. The original hits were filtered and narrowed down using the above criteria.

Quality Assurance
The evaluation process involved assessing the quality of the research articles and this was based on the Scottish Intercollegiate Guidelines Network (SIGN) checklist for critical appraisal [18] and expert review of the articles.

Data Analysis
On the basis of the inclusion and exclusion criteria, 19,065 articles including full articles and abstracts were initially found following a search of the databases. However, based on the use of various search terms, this was significantly narrowed to smaller numbers. Of these, 11 articles which met the requirements for selection were included in the review (Table 1).
The sample size of the studies ranged from 54 to 1019 while the length of study ranged from 12 weeks to 4 1 /2 years. The duration of diabetes of the patients in the studies ranged from 1 ± 2 to 12 ± 7 years (Mean ± SD).

Exenatide Twice Daily versus Placebo
Exenatide twice daily was compared to placebo in seven of the 11 studies [19][20][21][22][23][24][25] (Table 1). Participants in the exenatide groups with metformin as one of the background treatments showed statistically significant decrease in body weight in five of the studies [20][21][22][23][24] compared to placebo group. However, mean reductions in body weight were not statistically significant between exenatide and placebo groups in the studies by Gastaldelli et al. [19] and Liutkus et al. [25].
In addition, the exenatide group in all the seven studies showed statistically significant decrease in HbA1c compared with the placebo group except for one study [23], where HbA1c reduction was not significantly different between the two groups (p = 0.26).
There were no significant differences in lipid profile between the exenatide groups and the placebo group [20,22,24,25] except with respect to HDL cholesterol in the study by Kadowaki et al. [24]. That study showed that significant reduction in HDL cholesterol was statistically greater in both exenatide groups compared to placebo although no statistically significant difference was observed in total cholesterol, LDL-cholesterol and triglycerides. However, systolic and diastolic BP decreased significantly in the exenatide group compared to placebo group in two studies [20,22]. In another study [25], diastolic pressure was significantly reduced in both treatment groups, while systolic blood pressure remained relatively unchanged from baseline values.

Exenatide Twice Daily versus Other Controls
While one of the remaining 4 studies had placebo + lifestyle modification as control [26], the other 3 studies were not placebo controlled [27][28][29]. The interventions included; exenatide + lifestyle modification versus placebo + lifestyle modification with metformin and/or sulfonylurea as background treatment [25]; exenatide versus Glimepiride with metformin as background treatment [27,28]; exenatide versus premixd insulin aspart with metformin as background treatment [29].
In all the 4 studies [26][27][28][29] (Table 1), there were significantly better clinical outcomes in the exenatide groups compared with glimepiride, premixed insulin aspart, placebo plus lifestyle modification programme, based on the specific outcomes measured by each study (body weight, blood pressure, lipid profile and glycaemic control). For example, there was significant decrease in body weight in exenatide group compared to control groups in all the four studies.
With respect to HbA1c targets (<7% and <6.5%) exenatide twice daily was non inferior compared to premixed insulin aspart [29]. In addition, there were significant differences in favour of the exenatide groups compared with the glimepiride group with respect to HbA1c < 7% (p < 0.0001) and HbA1c < 6.5% (p = 0.0001) [28]. The percentage of hypoglycaemia in the exenatide group was significantly (p < 0.0001) lower than the glimepiride group [27,28]. When compared with the placebo plus lifestyle, the exenatide plus lifestyle groups had significantly more participants who had HbA1c ≤ 6.5% (p = 0.001) [26].
The study by Simo et al. [27] showed that a statistically significant proportion of exenatide treated patients achieved the HDL-cholesterol goal than glimepiride treated patients at 36 months (p = 0.021). In addition, systolic blood pressure (BP) [26][27][28] and diastolic BP [26,27] decreased significantly in the exenatide groups compared with controls.

Discussion
The exact mechanisms of the potential benefit of exenatide in the control of cardiovascular risks and complications are complex and still evolving [12,13]. However, the findings of this review would suggest that the influence of exenatide in possibly managing cardiovascular risks and complications may be through its effect in reducing glycated haemoglobin (HbA1c), reducing body weight and blood pressure. These are the markers of cardiovascular risk [27]. This view is supported by previous reports, which revealed that the probable effects of exenatide may be through glycaemic control based on the link between HbA1c and cardiovascular events and evidence that tight glycaemic control and/or decrease in HbA1c has been shown to reduce microvascular risks and complications [1,9,12].
High levels of glycated haemoglobin have been proposed as independent risk factors for patients with diabetes and those without diabetes [30]. In addition, higher HbA1c levels are known to be positively correlated with future risk of stroke and coronary heart disease, and that for every 1% rise in HbA1c, there is an associated 8% increased risk of first cardiovascular event [3,31]. In the present review, all the studies showed statistically significant decrease in HbA1c in the exenatide group compared to controls except in the study by Gill et al. [23]. Perhaps the sample size with only 54 participants in the Gill et al. [23] study was not large enough to elicit any statistically significant difference in the HbA1c level compared to the other studies with sample sizes ranging from 79 to 1019 participants. The Simo et al. [27] study had no report on HbA1c levels.
Another possible mechanism of the likely benefit of exenatide on cardiovascular risks and complications is its impact on body weight. Based on the results of the studies reviewed, it is clear that nine of the eleven studies showed significant decrease in body weight among participants in the exenatide group compared with placebo or control group. Only two studies [19,25] did not report statistically significant differences in body weight between exenatide group and control group. While one of these studies had no background treatment [19], the other had thiazolidinedione, metformin plus thiazolidinedione [25]. Therefore, it would appear that exenatide is more effective in reducing body weight in patients with type 2 diabetes when used in combination with metformin than when used alone or in combination with thiazolidinedione. Increases in body weight and body mass index in patients with type 2 diabetes have been reported to increase the risk of cardiovascualr diseases whereas reduction in body weight increases insulin sensitivity and reduces blood pressure [12,32]. In addition, exenatide twice daily is superior to insulin, sulfonylureas and rosiglitazone in decreasing body weight [9].
Another mechanism of the potential action of exenatide on cardiovascular risks and complications may be its effect on the pathogenic link between type 2 diabetes and atherosclerosis [13]. The formation of advanced glycation endproducts (AGE) in patients with type 2 diabetes plays a key role in vascular damage and exenatide has been reported to ameliorate this deleterious effects of AGEs [13].
According to Anagnostis et al. [13], the main mechanism of the antihypertensive role of exenatide may be due to its effect on weight loss although the authors also alluded to the vasodilatory effects of GLP-1. Although exenatide twice daily may improve blood pressure and certain lipid parameters, changes are often small and variable between studies [9,33]. In the present review, the studies, which looked at the effect of exenatide twice daily on lipid profile [20,22,[24][25][26][27][28], did not find any significant difference between the exenatide group and the control group except for HDL-cholesterol [24,27]. However, statistically significant decrease was observed between exenatide group and controls with respect to blood pressure (systolic and/or diastolic) in these studies.
With respect to glycaemic control, episodes of hypoglycaemia were less frequent in the exenatide group compared to glimepiride [27,28] and premixed basal insulin aspart [29] groups. This appears to be in tandem with previous reports which suggest that the incidence of hypoglycaemia is relatively low with exenatide treatment except when used in combination with a sulfonylurea due to their mechanism of action, which is glucose dependent [15].

Conclusions
Based on the findings of this review, it would appear that exenatide twice daily may be useful in managing cardiovascular risks and complications by reducing body weight, HbA1c and blood pressure. In particular, the combination of exenatide with metformin was more effective in reducing body weight than using exenatide alone.

Conflicts of Interest:
The author declares no conflict of interest.