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A REVIEW OF EXENATIDE – PROMISING ANTIDIABETIC AGENT FOR THE TREATMENT OF CARDIOVASCULAR PROBLEMS ASSOCIATED WITH DIABETIS MELLITUS TYPE 2

 


D Kapoor 1*, Vyas RB1, Lad C1, Patel M1, Tyagi BL2
1. Dr. Dayaram Patel Pharmacy College, Bardoli, Surat, Gujarat, India
2. Senior officer, Corporate Quality Assurance, Sun Pharmaceuticals Limited, Haridwar,Uttarakhand, India

ABSTRACT

Management of T2DMin obese patients is particularly challenging as treatment with the majority of glucose-lowering agents results in weight gain. Thus, the development of a therapeutic option which could improve glycemic control without weight gain or hypoglycemia, such as the glucagon-like peptide-1 (GLP-1) analog exenatide, is a welcome addition to the currently available therapies in the management of T2DM. With recognition and better understanding of the role of incretin hormones in T2DM, exenatide was developed and introduced into clinical practice in 2005. Both randomized controlled trials and retrospective observational studies have shown that treatment with exenatide not only improves glycemic control, with a low risk of hypoglycemia, but also results in concurrent weight loss and the additional benefit of improvement in cardiovascular risk factors.

Exenatide is a unique agent which can effectively control blood glucose levels in type 2 diabetes mellitus without producing dangerous adverse effects. In addition, it can lower body weight which is very essential for the treatment of obese type 2 diabetes mellitus patients. Since it can delay the destruction of islet beta-cells, type 2 diabetes mellitus patients are not rapidly converted to type 1 diabetes mellitus and ultimately appearance of complications of the disease is halted or delayed. In addition, current antidiabetic medications have significant side effects most of which include hypoglycemia and weight gain. Recently, new classes of agents targeting the incretin system have become available.

These can be divided into two broad categories; glucagon like peptide-1 (GLP-1) agonists/analogs (exenatide, liraglutide), and dipeptidyl peptidase-4 (DPP-4) inhibitors (sitagliptin, vildagliptin, and Saxagliptin (undergoing phase 3 trials)). Exenatide, a 39-amino acid peptide produced in the salivary gland of the Gila monster lizard, is a GLP-1 agonist. It is the first of its class approved for use as adjunctive therapy, in patients with Type 2 diabetes mellitus (T2DM). Current data suggests that exenatide, in combination with metformin, glyburide, or a glitazone, results in significant reductions in fasting and postprandial plasma glucose and hemoglobin A1c (HbA1c).

Apart form gastrointestinal side effects, exenatide is relatively well tolerated and does not cause hypoglycemia when used alone. Additionally, the drug serves to promote moderate weight loss. The authors aim to provide a comprehensive overview of exenatide, detail its mechanism of action, and discuss its role in the present day treatment of patients with T2DM.

Keywords: Antidiabetic agent, Exenatide, incretin-mimetic peptide Hormone, T2DM

INTRODUCTION

Type 2 diabetes mellitus (T2DM) is a progressive metabolic disorder, where, the currently used antidiabetic drugs could not retard the progression of the disease. Therefore, agents, effective in this respect, are needed which can delay such progression. Otherwise, diabetes-associated complications will appear within a short period and there is the possibility of such patients being converted to type 1 diabetes mellitus (T1DM) individuals. Combining these measures with pharmacological options early in the disease process is recommended, as adherence to lifestyle changes are short lived. However, as physicians, we must continue to stress strict adherence to lifestyle modification, as these changes have pleiotropic effects apart from glycemic control.1 Current approaches to improving glycemic control in diabetic populations include using medications which reduce hepatic glucose output (Metformin), increase insulin secretion (Sulfonylureaes, Meglitinides), augment insulin sensitivity(Glitazones), and reduce glucose absorption (Acarbose).

Lastly, insulin and its analogues also come into play. Exendin-4 (EX-4), an incretin-mimetic peptide hormone (containing 39 aminoacid residues) having GLP-1 like action, is secreted in the saliva (oral secretions) and concentrated in the tail of Gila monster lizard (Heloderma suspectum). This lizard takes food four times a year and during feeding, EX-4, secreted in the saliva, is thought to help its pancreas to switch on. Exenatide (EX) is a synthetic form of EX-4 which shares 53 per cent amino acid sequence similarity with naturally occurring hormone GLP-1 and acts as a GLP-1 receptor agonist.2-6 It has been observed that in such patients, weight loss decreases fasting and postprandial (pp) plasma glucose levels, glycosylated hemoglobin [HbA1c], and need for pharmacotherapy.

Unfortunately, most of the currently available antidiabetic drugs, including insulin, cause weight gain. Therefore, pharmacotherapy for obesity, as part of an integrated management plan, is beneficial for maintaining wt loss, optimising glycemic control and probably delaying progression of the disease.7 

Theory of Incretins:

Incretins are gut hormones produced by the small intestine in response to oral ingestion of glucose, which accounts for more than 50% of insulin secretion after food intake. These hormones include glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). The higher insulin response to orally administered glucose than to parenterally administered glucose is known as the incretin effect, which is deemed to be impaired in T2DM.8 In 1964, Elrick et al13 were the first of three groups to show that glucose, when given orally, induced a greater insulin response (by radioimmunoassay) than intravenous (i.v.) glucose injection. This was despite higher blood glucose levels attained because of the i.v. vs. oral glucose. This lead to the discovery of local gut hormones called incretins.

Subsequently in 1973, Brown and colleagues found that an enzyme that inhibited gastric acid secretion in dogs also had insulinotropic properties. They coinedthe term GIP (including both the synonyms gastric inhibitory peptide and glucose-dependent insulinotropic peptide). However GIP, did not fully account for the increase in insulin. In 1985, another peptide produced in gut, glucagon-like peptide-1 (GLP-1), was found to be a potent insulinotropic factor.There is emerging evidence suggesting that GLP-1 has a direct influence on myocardium and vascular endothelium, which could potentially improve cardiovascular outcomes, either via GLP-1R or independently of GLP-1R.9-13 The exact mechanism underlying the cardioprotective effect has not been fully elucidated. Some studies suggest an increased myocardial sensitivity to insulin and myocardial glucose uptake independently of plasma insulin level.

Other studies indicate an inhibition of cardiac myocyte apoptosis via inflammatory mediators and activation of antioxidant genes to reduce fibrosis and left ventricular remodeling, thus restoring left ventricular function after myocardial infarction. A review describes improvement in left ventricular function and myocardial oxygen consumption with GLP-1 infusion in chronic heart failure, myocardial infarction, coronary angioplasty, and coronary artery bypass graft, although study patient populations were small in number. GLP-1 produces a vasodilatory effect through nitric oxide (NO) production in the endothelium, a mechanism independent of GLP-1R, in an isolated mouse heart model. However, this vasodilatory effect is also observed regardless of the NO pathway, indicating a direct action of GLP-1 on vascular smooth muscle through the GLP-1R. Furthermore, administration of exenatide was found to be associated with a reduction of inflammatory mediators, such as the highsensitivity C-reactive protein.14-19 

Drug properties

Exenatide is a synthetic 39-amino-acid peptide amide with the same amino-acid sequence as exendin 4, a peptide isolated from lizard saliva that was found to act as a potent agonist of glucoregulatory activities to GLP1, including glucose- dependent enhancement of insulin secretion by β-cells2–4. Importantly, as stimulation of insulin secretion occurs only in the presence of elevated blood-glucose concentrations, the risk of hypoglycaemia, which is a problem with some other antidiabetic agents, such as sulphonyl ureas, should be reduced with exenatide. Exenatide also reduces food intake and slows gastric emptying, thereby reducing the rate at which meal-derived glucose reaches the circulation. Finally, exenatide lowers serum glucagon concentrations during periods of hyperglycaemia. In patients with diabetes, glucagon levels are inappropriately high during periods of hyperglycaemia, and lowering serum concentrations of glucagon during such periods leads to decreased hepatic glucose output and decreased insulin demand.20, 21 

GLP 1 Agonist:

The parent compound was derived from exendin, found in the saliva of the desert Gila monster (Heloderma suspectum). It shares approximately 50% homology with human GLP-1 and resists inactivation by the DPP-4 enzyme, resulting in a longer half-life (2.4 h) and duration of action (4–6 h). It is usually administered subcutaneously at a dose of 5 lg twice daily (BID) and titrated up to 10 lg (BID) after an initial 4 weeks. The second GLP-1 analog, liraglutide (Victoza), is a once-daily formulation, synthesized by recombinant DNA technology, sharing 97% homology with human GLP-1. It was recommended by the NICE in the technology appraisal guidance in 2010. Continuous GLP-1 administration is required for maintenance of glucose homeostasis because of its short halflife (1.5–2 min).

GLP-1 is degraded by dipeptidyl peptidase-4 (DPP-4). Hence, therapeutic options include analogues which provide supra physiological levels of GLP-1 and are resistant to cleavage by DPP-4, or agents which inhibit the activity of DPP-4. DDP-4 has effects beyond its proteolytic action, including T-cell proliferation, and is also widely expressed in human tissues including the brain, lungs, kidneys, adrenals, pancreas, and intestines. Thus, there is some concern that DDP-4 inhibitors may have pleiotropic effects unrelated to diabetes control and may contribute to side effects which are not initially seen in early clinical trials.22, 23 

Mechanism of action:

The amino acid sequence of exenatide shares a 50% sequence identity with human GLP-1, enabling exenatide to bind with and activate the human GLP-1 receptor in vitro. Binding triggers

cAMP mediated and/or other intracellular signaling pathways and results in the glucoregulatory actions of exenatide. Exenatide is impervious to DPP-IV inactivation, consequently giving it a longer duration of action. It promotes the first phase of insulin secretion and the suppression of glucagon, without hindering the counter regulatory hormonal response to hypoglycemia. In patients with type 2 diabetes, this first-phase insulin response is absent. As depicted by Figure 1, therapeutic plasma concentrations of exenatide significantly increase first-phase and second- Phase insulin secretion in response to an IV bolus of glucose, when compared with saline (P, 0.001 for both).24, 25 

Pharmacodynamics:

Exenatide has several mechanisms of action, the ultimate outcome being better glycemic control. Some of the actions are acute (immediate), glucose-dependent insulin secretion, suppression of pp high glucagon concentrations, delayed gastric emptying, inhibition of food intake, and modulation of glucose trafficking in peripheral tissues, while others appear late: weight loss, improved beta-cell mass and function. Exenatide increases pancreatic response to food leading to enhanced secretion of higher and more appropriate amount of insulin that assists in lowering the pp rise in blood sugar.

It controls the blood glucose concentration and can restore glucose stimulated insulin secretion without excess risk of hypoglycemia. Insulin itself and other antidiabetic drugs which produce their action by increasing the secretion of insulin, can cause dangerous hypoglycemia. But, Exenatide in spite of its insulin release-stimulating action does not do so. Hence, the compound ensures a relatively lesser risk of hypoglycemia, which is an advantage over many antihyperglycemic agents.26-30

 

Pharmacokinetics:

The bioavailability of exenatide after subcutaneous (s.c.) administration has been found to be 65-75 per cent (based on animal studies) (Table 1). After parenteral administration, it reaches a peak concentration in approximately 2 h with a duration of action up to 10 . When a dose of 10 mg is used, a maximum concentration (Cmax) of 211 pg/ml is achieved in 2.1 h (time taken to produce maximum response, i.e., tmax) along with a mean area under the curve (AUC) of 1036 pgh/ ml. After administration of a s.c. dose, the mean apparent volume of distribution is 28.3. The kidney (by glomerular filtration) is the primary route of elimination followed by degradation of EX by proteolysis. Its clearance value is 9.1 l/h. Its dosage adjustment is necessary only when creatinine clearance is below 30 ml/min or 1 l/h as found in severe renal failure (end stage renal disease).

Age, gender, race and body mass index do not seem to affect the pharmokinetics of exenatide. In patients with end stage kidney disease on dialysis, clearance of the drug is reduced to 0.9 L/hr. In those with mild to moderate renal impairment (creatnine clearance of 30 to 80 ml/min), clearance is shown to be only mildly reduced thus requiring no dose reduction. However, exenatide is not recommended in patients with creatinine clearance of less than 30 mls/min. At present, no data is available on exenatide use in patients with hepatic insufficiency as this is not expected to affect drug concentrations given that it is primarily renally cleared.31-34 

Drug interactions:

As exenatide delays gastric emptying, caution should be taken when the drug is co-administered with certain drugs like digoxin, lovastatin, lisinopril, acetaminophen, antiinfectives and oral contraceptives. It has been suggested to use these agents at least 1 h before the administration of exenatide with a light meal or snack (if needed).31

Contraindications:

Exenatide is not indicated in T1DM or diabetic ketoacidosis as it is not an insulin substitute. It has not been recommended for diabetics with end stage renal disease (creatinine clearance <30 ml/min) and severe gastrointestinal disorder (like gastroparesis).31, 35

Adverse effects:

Approximately 45 per cent of T2DM patients receiving exenatide were positive for antiexenatide

antibodies, with the majority of them having low titres range (<1/125). It has also been reported that in most patients antiexenatide antibody concentration is reduced over time. The occurrence of these titres did not seem to have a predictive effect on glycemic response or adverse events. These include, nausea, vomiting, diarrhea, jitteriness, dizziness, headache, dyspepsia, uneasiness, decrease in appetite, hypoglycemia (mainly when combined with a sulfonylurea), increased sweating and immunogenic reactions at the injection site. The chief adverse effects (in approximate percentage of occurrence) are nausea (44%), hypoglycemia (20%), diarrhea (13%) and vomiting (13%). By slowly escalating the dose (or when a target dose of exenatide is achieved in patients with gradual dose titration, dose-limiting gastrointestinal adverse events like nausea and vomiting can be minimized without loss of glucoregulatory activity.36-40 

Therapeutics uses:

Exenatide offers a unique treatment option for T2DM patients who are refractory to metformin or sulfonylurea or both. Considering all the actions, adjunctive therapy with EX is a valuable alternative in T2DM patients requiring moderate progress in glycemic control despite treatment with metformin and/or a sulfonylurea. The use of Exenatide with metformin and a sulfonylurea have been found to provide significant improvements in treatment satisfaction and patients’ health related quality of life. Exenatide is also considered to be an alternative therapy for those patients who cannot tolerate other antidiabetic drugs. In two open-label, randomized, multicentric comparative (insulin) controlled trials in T2DM patients suboptimally controlled with metformin and a sulfonylurea, treatment with Exenatide (5 μg twicedaily for 4 w and 10 μg thereafter) and an insulin analogue (glargine or biphasic insulin aspart) resulted in similar effects in HbA(1)c.

On the other hand, Exenatide produced decrease in body weight while insulin analogue caused weight gain. So, Exenatide is a treatment option in insulin-naïve patients with T2DM and who are overweight and suboptimally controlled by metformin and sulfonylurea Tsunnekawa et al reported that chronic s.c. treatment with Exenatide-4 resulted in signifi cant increase of the insulin contents of the pancreas and the insulin positive area was retained. From above-mentioned information it is clear that in addition to improvement in glycemic control in T2DM patients, Exenatide can reduce or eliminate the danger of hypoglycemia and weight gain. Since Exenatide therapy often leads to wt loss, this effect further assists in decreasing insulin resistance. It is difficult to get a drug which can lower blood glucose to an appropriate level without inducing a significant associated wt gain and can check the progression of diabetes (earlier it has been mentioned that Exenatide itself can halt progression of the disease). Exenatide and rimonabant are recently developed agents that have both glucose-lowering and body wt reducing properties.41-44 

Metabolic Effect of Exenatide on Glycemic Control and Body Weight:

In all the studies, addition of ExBID (10 lg) resulted in a significant improvement in glycemic control of approximately 1% and a dose-dependent progressive weight loss of approximately –1.5 to –3.0 kg. There was a statistically significant decrease in mean fasting plasma glucose of  0.6 mmol/L. The postprandial plasma glucose level was significantly reduced at week 4 and this was sustained up to 30 weeks in the standardized meal tolerance test, When the efficacy of ExBID was compared with TZDs in a meta-analysis including 22 studies over a 24-week period, TZDs were found to produce a greater improvement in glycemic control (reduction in HbA1c of –0.80 vs. –0.60%), whilst exenatide was associated with a reduction in body weight (–2.74 vs. ?2.19 kg). A significant reduction in fasting plasma glucose was observed only in those treated with TZDs, with a mean difference of –1.64 mmol/L.45-48 

Dose:

The initial recommended dose of EX (in combination with metformin or sulfonylureas) is 5 μg (s.c.) twicea- day, administered within 60 min before the morning and evening meals. The drug should not be injected postprandially. After 1 mo, the dose may be increased to 10 μg (s.c.) twice-daily which produces better diabetes management[60]. When EX is used with metformin in T2DM patients, metformin dose may not be adjusted. On the other hand, when it is administered with sulfonylurea, dose reduction of sulfonylurea should be considered because such combination is liable to cause more hypoglycemia. EX decreases insulin requirement in some patients and may delay the need to resume insulin in others. As has been mentioned earlier, EX is easier to administer than insulin because of its prefi lled pen design and simple dosing schedule.49-51

Long-acting EX:

One of the important drawbacks of EX therapy is its twice-daily parenteral administration. To overcome this disadvantage a long-acting injectable preparation of the compound has been formulated which can be used once-a-week[3,62], even once-a-month[5]. Long-acting release preparation of EX (EX LAR) is currently in the phase of clinical development. Several comparative clinical trial results have documented the similar beneficial results of this form of EX administered subcutaneously once-a-week/once in two weeks/once-a-month with that of EX, which is used twice-daily (BID).52

Clinical specifications:

HbA1c alone as a guide is an oversimplification of the metabolic con- sequences associated with diabetes, as this addresses only part of the clinical conundrum that we face when dealing with T2DM. Data showing improvements in definite macrovascular end points such as cardiovascular events and all cause mortality will take several years to show any difference given the chronicity of the disease. 

Weight loss and BMI:

GLP-1 analogues resulted in weight loss in all clinical trials. With respect to placebo, the difference in endpoint BMI was -0.35 [-1.14;-0.10] kg/m2. With comparison to insulin, the difference was even larger (-1.57 [-1.98; -1.15] kg/m2; P, 0.001). There was no strong co relationship between side effects of nausea and weight loss. Participants who did not report nausea also lost weight.

Cardiovascular effects:

Although no studies with subcutaneous exenatide exists, I.V. infusion of GLP-1 agonists in post MI patients with reduced EF, CABG, and heart failure showed improvement in cardiovasular outcomes. These include improvement in EF quality of life and 6 minute walk test and the reduced use of ionotropes. The benefits seen were similar in patients with and without diabetes; however the number of subjects in these studies was small (all less than 20). The studies themselves were of short duration. Nevertheless, they should pave the way for further trials. The above data should not be confused with the effect of tight glycemic control on the rates of major cardiovascular events. As noted above, the relationship between a reduction in HbA1c and cardiovascular events has always been a contentious issue.55-57

Metabolic parameters:

Two opened labeled trials have shown that exenatide positively impacts other risks factors. In the first study in which analyses were conducted on data from all subjects who had the opportunity to achieve 2 years of exenatide exposure, irrespective of their treatment arm in the 30-week placebo- controlled trials. Patients with elevated ALT at baseline (151/283 [53%]) had a mean (SEM) reduction of ALT (-11 IU/L from baseline 38 [1] IU/L; P, 0.05) and 39% achieved normal ALT by week 104. Furthermore, beta-cell function as measured by the homeostasis model assessment (HOMA-B), blood pressure, and aspartate aminotransferase (AST) all have improved.

However, of a total of 974 patients enrolled in this 2-year extension phase, four hundred fifty- three patients were excluded due to late enrollment date and site closure. Of the remaining 521 patients that were considered eligible, only 283 completed the study. Also the percentage of patients on ACE inhibitors, statins and Aspirin, which are now the standard of care, was very low (37%–39%). The same group reported lipid profiles in a sub group of patients (151) who completed the three and a half year study period and found a 12% reduction in triglycerides, a 5% reduction in total cholesterol, a 6% decrease in low density lipoprotein (LDL), and an increase in high density lipoprotein (HDL-C) by 24%.46 Similar effects were seen in a retrospective data analysis of approximately 300 patients.58, 59

Glycemic control:

All available randomized controlled trials (RCTs) either published or unpublished showed similar results (HbA1c in comparison with placebo (-1.0 [-1.1: -0.8]). These meta analyses included studies ranging from 12 weeks to 30 weeks duration in the case of the first meta analysis and up to a year in the second meta analysis. However open-label extension studies have shown maintain of reduction of HbA1c up to 82 weeks. Of note, 92 patients of the 150 cohorts completed the full duration of treatment in the second study group.

There has been some controversy regarding the effect of GLP-1 agonist on long term beta cell dysfunction. Animal studies have shown GIP has antiapoptotic properties and may indeed increase beta cell mass, the holy grail of diabetic treatment. This theory has been tested by a small RCT comparing exenatide to insulin as an add on to metformin for a year. They found treatment induced change in combined glucose and arginine stimulated C- peptide secretion was 2.46 fold [95% CI, 2.09 to 2.90, P , 0.0001] greater following 52-week exenatide treatment as compared to insulin glargine. Both exenatide and insulin glargine reduced hemoglobin HbA1c similarly: -0.8 ± 0.1% and -0.7 ± 0.2% respectively. Exenatide reduced body weight compared to insulin glargine (difference -4.6 kg, P, 0.0001).60-64

Blood Pressure:

The mechanism for lowering blood pressure by exenatide appears to be related to weight loss. However, in salt-sensitive rodent models, GLP-1 treatment has been shown to have antihypertensive, cardioprotective, and renoprotective actions through natriuretic and diuretic effects.As discussed previously, the action on endothelium and vascular smooth muscle, producing vasodilatory effects, may contribute to lowering of the blood pressure. In the HEELA study, there was a significant decrease in SBP with ExBID treatment, which was statistically and significantly different from the change with insulin glargine (–3.6 mmHg, P = 0.034). Both SBP (–2.7 mmHg) and DBP (–1.7 mmHg) decreased significantly from baseline and heart rate increased by 2.3 beats/ min when ExBID was added to basal insulin glargine. The difference was also significant when compared to the placebo. Both ExBID and liraglutide reduce SBP and DBP; however, the increase in heart rate was significantly higher with liraglutide (3.28 vs. 0.69 beats/min, P = 0.0012).65-68 

Effectiveness of exenatide in comparison of oral antidiabetic agent:

In all the studies, addition of ExBID (10 lg) resulted in a significant improvement in glycemic control of approximately 1% and a dose-dependent progressive weight loss of approximately –1.5 to –3.0 kg. There was a statistically significant decrease in mean fasting plasma glucose of –0.6 mmol/L. The postprandial plasma glucose level was significantly reduced at week 4 and this was sustained up to 30 weeks in the standardized meal tolerance test. When the efficacy of ExBID was compared with TZDs in a meta-analysis including 22 studies over a 24-week period, TZDs were found to produce a greater improvement in glycemic control (reduction in HbA1c of –0.80 vs. –0.60%), whilst exenatide was associated with a reduction in body weight (–2.74 vs. ?2.19 kg). A significant reduction in fasting plasma glucose was observed only in those treated with TZDs, with a mean difference of –1.64 mmol/L. When ExBID was added to a TZD, the combination was also found to be effective.

TZDs are insulin sensitizers, which improve insulin action in muscle and adipose tissue with some reduction in hepatic glucose production. These complementary mechanisms rationalize the potential use of combining the two in management of T2DM. In a double-blind, placebo-controlled trial, patients with T2DM who were suboptimally controlled with TZD (with or without metformin) were investigated over a period of 16 weeks Addition of ExBID resulted in a placebo-subtracted reduction in HbA1c of 0.98% and a significant weight loss of –1.51 kg (P\0.001). However, this study was of relatively short duration. Liutkuz et al. reported a similar improvement in glycemic control in a study over a 26-week period.69-73 

Effectiveness of exenatide as substitute therapy of insulin:

In a head-to head, open-label study, 551 patients with T2DM who were not adequately controlled on metformin or a SU were randomized to receive treatment with either ExBID or basal insulin glargine over 26 weeks. Both treatments produced a comparable reduction in HbA1c of 1.11%. However, there was a significant difference in body weight of –4.1 kg between the two groups, a decrease of –2.3 kg with ExBID and an increase of ?1.8 kg with glargine. A similar efficacy in glycemic control with divergent effects on body weight in favor of ExBID were also reported in another multicenter, randomized, open-label, parallelcomparator study (Helping Evaluate Exenatide in patients with diabetes compared with Long- Acting insulin [HEELA]).

A smaller study with a longer duration of 52 weeks also reported similar results. Barnett and colleagues conducted a crossover study where 138 patients were randomized to receive either ExBID followed by insulin glargine or vice versa over successive 16-week periods. Glycemic control improved in both groups by 1.36%; however, patients lost weight while on ExBID and gained weight on insulin glargine, with a difference of –2.2 kg. In all three studies, ExBID reduced prandial glucose excursions more than glargine, while glargine reduced fasting glucose concentrationsmore than ExBID. When compared to treatment with biphasic insulin aspart, both treatments showed similar improvements in HbA1c of approximately 1%, but showed a weight difference of –5.4 kg in favor of ExBID.74-78  

Efficacy of ExER Compared to a DPP-4 Inhibitor, TZD, and Metformin:

The study investigated the safety and efficacy of ExER against the maximum approved dose of a DPP-4 inhibitor or TZD in patients treated with metformin. In this double-blind, superiority trial, patients were randomized into either an ExER (2 mg), a sitagliptin (100 mg), or a pioglitazone (45 mg) arm. Treatment with ExER reduced HbA1c (–1.5%) more significantly than sitagliptin (–0.9%) or pioglitazone (–1.2%). The reduction in fasting glucose was significantly greater with ExER (–1.8 mmol/L) than with sitagliptin (–0.9 mmol/L), but not with pioglitazone (–1.5 mmol/L). Similarly, a greater reduction in body weight was observed with ExER, a treatment difference of –1.5 kg with sitagliptin (P = 0.0002) and –5.1 kg with pioglitazone (P\0.0001) Thus, the addition of ExER to metformin achieved better glycemic control and weight loss than sitagliptin or pioglitazone. 

CONCLUSION

Exenatide is a artificial GLP-1 receptor agonist. When administered subcutaneously, it was found to augment glucose-dependent insulin secretion, restraint of pp high glucagon concentration, postponed gastric emptying, reticence of food intake, intonation of glucose trafficking in peripheral tissues and wt loss with mild to moderate hypoglycemia and gastrointestinal adverse effects. Incretin-based therapies, particularly GLP-1 analogs, offer an alternative option to currently available therapeutic agents in the management of T2DM. Treatment with either ExER or ExBID results in improvement in glycemic control comparable to any other existing agents, without increased risk of major hypoglycemia, and is associated with significant weight loss. It is generally well tolerated, and GI intolerance usually subsides a few weeks after initiation. There is also a trend of improvement in blood pressure and lipid profile, both of which could potentially offer a reduction in cardiovascular events.

REFERENCES 

  1. Patel SK, Goyal RK, Anand IS, Shah JS, Patel HU, Patel CN. Glucagon like peptide-1: A new therapeutic target for diabetes mellitus. Indian J Pharmacol 2006; 38:231-7.
  2. Mudaliar S. New frontiers in the management of type 2 diabetes. Indian J Med Res 2007; 125:275-96.
  3. Available from: http://www.wikipedia.org/wiki/Exenatide. [accessed on 2007 Jul 2].
  4. Kaushal S, Chopra SC, Arora S. Exenatide: An incretin-mimetic agent. Indian J Pharmacol 2006; 38:76-8.
  5. Available from: http://www.diabetessuffolk.com/Drugs/Exenatide.htm[accessed on 2007 Dec 20].
  6. Schnabel CA, Fineberg SE, Kim DD. Immunogenicity of xenopeptide hormone therapies. Peptides 2006; 27:1902-10.
  7. Gagliardi L, Wittert G. Management of obesity in patients with type 2 diabetes mellitus. Curr Diabetes Rev 2007; 3:95-101.
  8. Nauck M, Vardarli I, Deacon CF, et al. Secretion of glucagon-like peptide-1 (GLP-1) in type 2 diabetes: what is up, what is down? Diabetologia. 2011; 54: 10–8.
  9. Elrick H, Stimmler L, Hlad CJ Jr, Rai Y. Plasma insulin response to oral and intravenous glucose administration. J Clin Endocrinol Metab. 1964; 24:1076–82.
  10. McIntyre N, Holdsworth CD, and Turner DS. New interpretation of oral glucose tolerance. Lancet. 1964;2:20–1.
  11. Perley MJ, Kipnis DM. Plasma insulin responses to oral and intravenous glucose: studies in normal and diabetic sujbjects. J Clin Invest. 1967; 46: 1954–62.
  12. Dupre J, Ross SA, Watson D, Brown JC. Stimulation of insulin secretion by gastric inhibitory polypeptide in man. J Clin Endocrinol Metab. 1973; 37: 826–8.
  13. Schmidt WE, Siegel EG, Creutzfeldt W. Glucagon-like peptide-1 but not glucagon-like peptide-2 stimulates insulin release from isolated rat pancreatic islets. Diabetologia. 1985;28:704–7.
  14. Bhashyam S, Fields AV, Paterson B, et al. Glucagonlike peptide-1 increases myocardial glucose uptake via p38alpha MAP kinase-mediated, nitric oxidedependent mechanisms in conscious dogs with dilated cardiomyopathy. Circ Heart Fail. 2010; 3: 512–21.
  15. Liu X, Pachori AS, Ward CA, et al. Heme oxygenase- 1 (HO-1) inhibits postmyocardial infarct remodeling and restores ventricular function. FASEB J. 2006; 20:207–16.
  16. Anagnostis P, Athyros VG, Adamidou F, et al. Glucagon-like peptide-1-based therapies and cardiovascular disease: looking beyond glycaemic control. Diabetes Obes Metab. 2011; 13:302–12.
  17. Ban K, Noyan-Ashraf MH, Hoefer J, et al. Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptordependent and -independent pathways. Circulation. 2008; 117:2340–50.
  18. Nystro¨m T, Gonon AT, Sjo¨holm A, et al. Glucagonlike peptide-1 relaxes rat conduit arteries via an endothelium-independent mechanism. Regul Pept. 2005; 125:173–7.
  19. Chilton R, Wyatt J, Nandish S, et al. Cardiovascular comorbidities of type 2 diabetes mellitus: defining the potential of glucagon-like peptide-1-based therapies. Am J Med. 2011; 124:S35–53.
  20. Joy, S. V. et al. Incretin mimetics as emerging treatments for type 2 diabetes. Pharmacother. 2005; 39, 110–118
  21. Green BD, Flatt PR, Bailey CJ. Dipeptidyl peptidase IV (DPP IV) inhibitors: a newly emerging drug class for the treatment of type 2 diabetes. Diab Vasc Dis Res. 2006; 3:159–65.
  22. Barnett AH. New treatments in type 2 diabetes—a focus on the incretinbased therapies. Clin Endocrinol (Oxf). 2009; 70:343–53.
  23. Triplitt C, Chiquette E. Exenatide: from the Glia moster to the pharmacy. J Am Pharm Assoc. 2006; 46:44–55.
  24. Physicians Desk Reference. Byetta® (exenatide) Injection. PDR Network, 2010. http://www.pdr.net/druginformation/DocumentSearchn_Local.
  25. Jeppesen CB, et al. Differential structural properties of GLP-1 and exendin-4 determine their relative affinity for the GLP-1 receptor N-terminal extra cellular domain. Biochemistry 2007; 46:5830-40.
  26. Nielsen LL, Young AA, Parkes DG. Pharmacology of exenatide (synthetic exendin-4): A potential therapeutic for improved glycemic control of type 2 diabetes. Regul Pept 2004; 117:77 88.
  27. Chen D, Liao J, Li N, Zhou C, Liu Q, Wang G, et al. A nonpeptide agonist of glucacon-like peptide 1 receptors with effi cacy in diabetic db/db mice. Proc Natl Acad Sci USA 2007; 104:943-8.
  28. Schnabel CA, Wintle M, Kolterman O. Metabolic effects of the incretin mimetic exenatide in the treatment of type 2 diabetes. Vasc Health Risk Manag 2006; 2:69-77.
  29. Barnett AH. Exenatide. Drugs Today 2005; 41:563-78.
  30. Kaushal S, Chopra SC, Arora S. Exenatide: An incretin-mimetic agent. Indian J Pharmacol 2006; 38:76-8.
  31. Nolte MS, Karam JH. Pancreatic hormones and diabetic drugs. In: Katzung BG, editor. Basic and Clinical Pharmacology. 10th ed. Boston: McGraw-Hill; 2007; 683-705.
  32. Copley K, Mc Cowen K, Hiles R, Nielsen LL, Young A, Parkes DG. Investigation of exenatide elimination and its in vivo and in vitro Curr Drug Metab 2006; 7:367-74.
  33. Bray GM. Exenatide. Am J Health Syst Pharm 2006; 63:411-8.
  34. Mudaliar S. New frontiers in the management of type 2 diabetes. Indian J Med Res 2007; 125:275-96.
  35. Ezzo DC, Ambizas EM. Exenatide injection (Byetta): Adjunctive therapy for glycemic control. Am Fam Physician 2006; 73:2213-4.
  36. Lam S, See S. Exenatide: A novel incretin mimetic agent for treating type 2 diabetes mellitus. Cardiol Rev 2006; 14: 205-11.
  37. Iltz JL, Baker DE, Setter SM, Keith Campbell R. Exenatide: An incretin mimetic for the treatment of type 2 diabetes mellitus. Clin Ther 2006; 28: 652-65.
  38. Barnett A. Exenatide. Expert Opin Pharmacother 2007; 8: 2593-608.
  39. Joy SV, Rodgers PT, Scates AC. Incretin mimetics as emerging treatment for type 2 diabetes. Ann Pharmacother 2005; 39:110-8.
  40. Tsunekawa S, Yamamoto N, Tsukamoto K, Itoh Y, KanekoY, Kimura T, et al. Protection of pancreatic beta-cells by exendin-4 may involve the reduction of endoplasmic reticulum stress; in vivo and in vitro J Endocrinol 2007;193:65-74.
  41. Sheffi eld CA, Kane MP, Busch RS. Off-label use of exenatide for the management of insulin-resistant type 1 diabetes mellitus in an obese patient with human immunodefi ciency virus infection. Pharmacotherapy 2007; 27:1449-55.
  42. Green JB, Feinglos MN. Exenatide and rimonabant: New treatments that may be useful in the management of diabetes and obesity. Curr Diab Rep 2007; 7: 369-75.
  43. Glass LC, Qu L, Lenox S, Kim D, Gates JR, Brodows R, et al. Effects of exenatide versus insulin analogues on weight change in subjects with type 2 diabetes: A pooled post-hoc analysis. Curr Med Res Opin 2008; 24: 639-44.
  44. DeFronzoRA,RatnerRE,HanJ,etal.Effectsofexenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care. 2005; 28:1092–100.
  45. Buse JB, Henry RR, Han JJ, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care. 2004; 27:2628–35.
  46. Kendall DM, Riddle MC, Rosenstock J, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care. 2005; 28:1083–91.
  47. Pinelli NR, Cha R, Brown MB, et al. Addition of thiazolidinedione or exenatide to oral agents in type 2 diabetes: a meta-analysis. Ann Pharmacother. 2008; 42:1541–51.
  48. Virji A. Use of exenatide for weight loss in patients with diabetes. Am
  49. Fam Physician 2007; 75:1304.
  50. Bond A. Exenatide (Byetta) as a novel treament option for type 2 diabetes mellitus. Proc (Bayl Univ Med Cent) 2006; 19:281-4.
  51. Ghofaili KA, Fung M, Ao Z, Melocho M, Shopiro RJ, Warnock GL, et al. Effect of exenatide on beta cell function after islet transplantation in type 1 diabetes. Transplantation 2007; 83:24-8.
  52. Kim D, Mac Conell L, Zhuang D, Kothare PA, Trautmann M, Finemann M, et al. Effects of once-weekly dosing of a long-acting release formulation of exenatide on glucose control and body weight in subjects with type 2 diabetes. Diabetes Care 2007; 30:1487-93.
  53. Amori RE, Lau J, Pittas AG. Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis. JAMA. 2007; 298: 194–206.
  54. Monami M, Marchionni N, Mannucci E. Glucagon-like peptide-1 receptor agonists in type 2 diabetes: a meta-analysis of randomized clinical trials. Eur J Endocrinol. 2009 Mar 24. [Epub ahead of print].
  55. Effects of Glucagon-Like Peptide-1 in Patients With Acute Myocardial Infarction and Left Ventricular Dysfunction After Successful Reperfusion. Circulation. 2004; 2;109(8):962–5.
  56. George G, Sokos DOa, Hakki Bolukoglu MDa, Judy German RN. Effect of Glucagon-Like Peptide-1 (GLP-1) on Glycemic Control and Left Ventricular Function in Patients Undergoing Coronary Artery Bypass Grafting.The American Journal of Cardiology. 2007 Sep 1;100(5):824–9.
  57. Sokos GG, Nikolaidis LA, Mankad S, Elahi D, Shannon RP. Glucagon- Like Peptide-1 Infusion Improves Left Ventricular Ejection Fraction and Functional Status in Patients With Chronic Heart Failure. J Card Fail. 2006; 12(9):694–9.
  58. Buse JB, klonoff DC, Nielsen LL, et al. Metabolic Effects of two years of Exenatide Treatment on Diabetes, Obesity, and Hepatic biomarkers in patients with Type 2 Diabetes; An Interim Analysis of Data from the Open—Label, Uncontrolled Extension of Three Double—Blind, Placebo- Controlled Trials. Clinical Therapeutics. 2007; 29(1):139–53.
  59. Bhushan R, Elkind-Hirsch KE, Bhushan M, Butler WJ, Duncan K, Marrioneaux O. Exenatide use in the management of metabolic syndrome: a retrospective database study. Endocr Pract. 2008 ;14(8):993–9.
  60. Kim SJ, Nian C, Widenmaier S, McIntosh CH. Glucose-dependent insulinotropic polypeptide-mediated up-regulation of beta-cell antiapoptotic Bcl-2 gene expression is coordinated by cyclic AMP (cAMP) response element binding protein (CREB) and cAMP-responsive CREB coactivator 2. Mol Cell Biol. 2008b; 28:1644–6.
  61. Bunck MC, Diamant M, Cornér A, et al. One-Year Treatment With Exenatide Improves Beta-Cell Function, Compared To Insulin Glargine, In Metformin Treated Type 2 Diabetes Patients: A Randomized, Controlled Trial. Diabetes Care. 2009 Feb 5. [Epub ahead of print].
  62. Monami M, Marchionni N, Mannucci E. Glucagon-like peptide-1 receptor agonists in type 2 diabetes: a meta-analysis of randomized clinical trials. Eur J Endocrinol. 2009 Mar 24. [Epub ahead of print].
  63. Riddle MC, Henry RR, Poon TH, et al. Exenatide elicits sustained glycaemic control and progressive reduction of body weight in patients with type 2 diabetes inadequately controlled by sulphonylureas with or without metformin. Diabetes Metab Res Rev. 2006; 22(6):483–91.
  64. Ratner RE, Maggs D, Nielsen LL, et al. Long-term effects of exenatide therapy over 82 weeks on glycaemic control and weight in over-weight metformin-treated patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2006; 8(4):419–28.
  65. Davies MJ, Donnelly R, Barnett AH, et al. Exenatide compared with long-acting insulin to achieve glycaemic control with minimal weight gain in patients with type 2 diabetes: results of the Helping Evaluate Exenatide in patients with diabetes compared with Long-Acting insulin (HEELA) study. Diabetes Obes Metab. 2009; 11:1153–62.
  66. Buse JB, Bergenstel RM, Glass LC, et al. Use of twice daily exenatide in basal insulin-treated patients with type 2 diabetes. A randomised controlled trial. Ann Intern Med. 2011; 154:1–10.
  67. Buse JB, Rosenstock J, Sesti G, et al. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet. 2009; 274:39–47.
  68. Hirata K, Kume S, Araki S, et al. Exendin-4 has an anti-hypertensive effect in salt-sensitive mice model. Biochem Biophys Res Commun. 2009; 380:44–9.
  69. DeFronzoRA,RatnerRE,HanJ,etal.Effectsofexenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 Diabetes Care. 2005; 28:1092–100.
  70. Buse JB, Henry RR, Han JJ, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care. 2004; 27:2628–35.
  71. Kendall DM, Riddle MC, Rosenstock J, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care. 2005; 28:1083–91.
  72. Zinman B, Hoogwerf BJ, Garcia SD, et al. The effect of adding exenatide to a thiazolidinedione in suboptimally controlled type 2 diabetes. Ann Intern Med. 2007; 146:477–85.
  73. Pinelli NR, Cha R, Brown MB, et al. Addition of thiazolidinedione or exenatide to oral agents in type 2 diabetes: a meta-analysis. Ann Pharmacother. 2008; 42:1541–51.
  74. Pinelli NR, Cha R, Brown MB, et al. Addition of thiazolidinedione or exenatide to oral agents in type 2 diabetes: a meta-analysis. Ann Pharmacother. 2008; 42:1541–51.
  75. Heine RJ, Van Gaal LF, Johns D, et al. Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes. Ann Intern Med. 2005; 143:559–69.
  76. Davies MJ, Donnelly R, Barnett AH, et al. Exenatide compared with long-acting insulin to achieve glycaemic control with minimal weight gain in patients with type 2 diabetes: results of the Helping Evaluate Exenatide in patients with diabetes compared with Long-Acting insulin (HEELA) study. Diabetes Obes Metab. 2009; 11:1153–62.
  77. Bunck M, Diamant M, Corner A, et al. One year treatment with exenatide improves b-cell function, compared with insulin glargine, in metformin treated type 2 diabetic patients. Diabetes Care. 2009; 32:762–8.
  78. Barnett AH, Burger J, Johns D, et al. Tolerability and efficacy of exenatide and titrated insulin glargine in adult patients with type 2 diabetes previously uncontrolled with metformin or a sulphonylurea: a multinational, randomized, open-label, twoperiod, crossover noninferiority trial. Clin Ther. 2007; 29:2333–48.
  79. Bergenstal RM, Wysham C, MacConell L, et al. Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct tometformin for treatment of type 2 diabetes (DURATION-2): a randomised trial. Lancet. 2010; 376:431–9.