The Prescription of Exenatide for Adults Type-2 Diabetes Patients on Insulin Therapy - Literature review Example

?Evidence to Support the Prescription of Exenatide for Adults Type-2 Diabetes Patients on Insulin Therapy Introduction The homeostasis of glucose in human body is mainly regulated by an interplay of several hormones. The interplay is complex and involves hormones like insulin, amylin and glucagon from pancreas and glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 or GLP-1 from gut (Hood et al, 2006). However, despite awareness of this, most of the therapeutic interventions for type-2 diabetes are aimed at abnormal secretion and signaling of the insulin, thus giving scope for poor control in some situations. Exenatide, a GLP analogue, is a recently approved drug for use in diabetic patients. It has been recommended as an adjunctive therapy to sulfonylurea and metformin regimens. In insulin dependent patients with type 2 diabetes, especially with obesity, control of glycemia is a challenging issue (Hood et al, 2006). Intensification of insulin therapy to achieve target levels of glycosylated hemoglobin leads to further weight gain. Infact, one of main anxieties with insulin therapy in this population is poor weight gain (Nayak et al, 2010). In several developed countries like UK, there are recommendations for obesity surgery, along with exercise, diet and drug control of diabetes. However, obesity surgery is associated with significant risk. Exenatide, when given as an adjunct to insulin therapy, has been proven to not only achieve better control of blood glucose levels, but also decrease the chances of gaining weight. Infact, some studies have demonstrated weight loss with exenatide therapy. In this article, evidence to support the prescription of exenatide, as an adjunct to insulin therapy will be discussed through review of suitable literature. Understanding the pathophysiology and treatment basis of diabetes type-2 Diabetes mellitus can be defined as a group of clinical syndromes characterized by hyperglycemia arising as a result of absolute or relative insulin deficiency (Edwards et al, 2002). There are basically 2 types of diabetes mellitus. While type-1 is due to absolute insulin deficiency as a result of pancreatic beta-cell destruction, there is relative insulin deficiency in type-2 as a result of combination of peripheral resistance to insulin action and an inadequate secretory response by the beta cells (Kumar et al, 2007). Type 2 diabetes is the most common form of diabetes constituting 90% of diabetic population (Ramachandran et al, 2002). In a classic definition, type 2 diabetes has been defined as a triad of 3 etiologies, namely, resistance to insulin, progressive failure or exhausion of beta cells, and increased gluconeogenesis at liver. However, there is another pathophysiologic abnormality that is worth mentioning and that is decreased activity of GLP-1 (Jellinger, 2011). The impaired insulin secretion in type-2 diabetes is due to beta cell dysfunction (DeFronzo, 1997). The beta cells fail to adapt themselves for the long-term demands of peripheral insulin resistance and increased insulin secretion (Kumaret al, 2007). In type-2, this dysfunction is both quantitative and qualitative. There is loss of normal pulsatile, oscillating pattern of insulin secretion and the rapid first phase of insulin secretion which is a normal response to elevated plasma glucose is attenuated. There is also decrease in beta cell mass, islet degeneration and deposition of islet amyloid (Kumaret al, 2007). Infact, studies have established the onset of insulin resistance much before the manifestations of hyperglycemia (DeFronzo, 1997). The pancreas beta-cell function declines gradually over time already before the onset of clinical hyperglycaemia (Stumvoll et al, 2005). The factors which probably lead to insulin resistance are increased non-esterified fatty acids, inflammatory cytokines, adipokines, and mitochondrial dysfunction for insulin resistance, and glucotoxicity, lipotoxicity, and amyloid formation for beta-cell dysfunction (Stumvoll et al, 2005). The fasting insulin levels in patients with type-2 diabetes may be either normal or increased and the basal insulin levels increased (DeFronzo, 1997). As the glucose concentration of the blood increases, the insulin levels also increase initially but after a certain range, beyond 140mg/dl, the insulin secretion is not sustained and the fasting insulin concentration declines precipitously. It is at this point that hepatic glucose production begins to rise and the hormone will not be able to suppress hepatic gluconeogenesis (Kumar et al, 2007). Thus the natural history of type-2 diabetes can be described as that starting with normal glucose tolerance, insulin resistance, and compensatory hyperinsulinemia with progression to impaired glucose tolerance (IGT) and overt diabetes mellitus and it can be said that hyperinsulinemia precedes the development of type 2 diabetes and hyperinsulinemia is a strong predictor of the development type 2 diabetes (Edwards et al, 2002). The main aims of treatment for type-2 diabetes are control of blood sugar and reduction in secondary complications associated with diabetes. This is because; over a period of time, persistent hyperglycemia leads to various microvascular and macrovascular complications. The microvascular complications are nephropathy, retinopathy and neuropathy. The macrovascular complications are cardiovascular diseases like ischemic heart disease and stroke. The risk of developing such complications is directly proportional to the duration of exposure to hyperglycemia. The initial treatment for diabetes involves patient education regarding lifestyle changes like reduction of weight, increased physical activity and appropriate dietary modification. When these changes fail to lower blood glucose levels, oral hypoglycemic agent, usually metformin is initiated. Further on, sulphonylureas are considered, when there is lack of adequate response, contraindication or intolerance to metformin. Sulphonylureas have significant side effects like hypoglycemia and weight gain and this may affect patient compliance and in turn affect overall glycaemic control. Glycosylated hemoglobin of more than 7 percent indicates inadequate control of diabetes (Shyangdan et al, 2010). Currently, the next step in the management of diabetes type-2 when oral hypoglycaemic therapy is inadequate is insulin therapy. Insulin therapy often results in hypoglycemic episodes and weight gain, and fails to achieve proper plasma glucose control in many cases. Thus, the existing treatments for type-2 diabetes patients are actually unsatisfactory and many patients, who do not have appropriate glycaemic control have increased risk of complications. Hence newer and better treatments are warranted (Shyangdan et al, 2010). GLP-1 analogues are a class of glucose lowering agents which are administered through injection. These drugs mimic the action of endogenous GLP-1, an incretin, that is released in response to food. The hormone mainly regulates plasma glucose levels by stimulating insulin biosynthesis and secretion that is dependent on glucose and also by suppressing secretion of glucagon, delaying gastric emptying and by promoting satiety. The action of GLP-1 analogues is mainly dependent on the plasma glucose levels. Thus, the effects of these drugs is most pronounced when there is hyperglycemia and the chances of induction of hypoglycemia with these drugs is minimal. Infact, several GLP-1 analogues like exenatide have been associated with weight loss (Shyangdan et al, 2010). Currently, there are six GLP-1 analogues, of which, only two, namely, exenatide and liraglutide are available in the market. other drugs, albiglutide, taspoglutide, lixisenatide and LY2189265 are in the pipeline. Exenatide is available as Byetta (Shyangdan et al, 2010). According to the NICE guidelines of the UK, GLP-1 analogues must be used as third line antihypoglycemic agents. In the United states however, they are used as second line drugs (Shyangdan et al, 2010). Evidence Exenatide has been evaluated by 3 major 30 week trials in patients with uncontrolled type 2 diabetes and on maximum oral hypoglycemic therapy. The trials were placebo controlled. Adjunct treatment with 10 micrograms of exenatide twice daily was associated with significant decrease in the mean glycosylated hemoglobin (by 1%) and fall in body weight (1.6- 2.8 kg) when compared to placebo therapy (Buse et al, 2004). The adverse effects noted in these trials were of mild to moderate intensity. The most common adverse effect was hypoglycemia, that too of mild to moderate intensity. Open label extension studies pertaining to exenatide showed than the effects of the drug on glycosylated hemoglobin and weight sustained over a good duration of time. Infact, a 82 week cohort study proved that administration of exenatide twice a day also caused significant fall in diastolic blood pressure, serum cholesterol levels and serum triglyceride levels. Changes associated with other important parameters like systolic blood pressure, total cholesterol and LDL cholesterol were not significant. Thus, adjunct therapy with exenatide twice a day is associated with several benefits and minimal side effects (Buse et al, 2004). With reference to adjunct to insulin therapy, there are actually not many trials studying the benefits of exenatide treatment with insulin. Whatever few studies have been done so far, favour exenatide therapy with insulin. Nayak et al (2010) conducted a prospective study to assess the benefits and effectiveness of administration of exenatide in diabetes patients with obesity treated with insulin. The study included 174 patients enrolled consecutively. All the patients had diabetes and obesity and were on insulin treatment. Prior to initiation of exenatide treatment, baseline recording of weight, body mass index, serum fructosamine, total cholesterol, HDL-cholesterol and doses of insulin administered were recorded. The patients were given 10 microgram of exenatide twice a day before breakfast and before dinner. The patients were followed up at 3 months, 6 months and 12 months time. 14 patients discontinued the therapy due to side effects. From the results of the study, it was evident that mean weight loss due to treatment was 10.7?±?5.7?kg and 12.8?±?7.5?kg (P? Read More