Use Of Dulaglutide And Sitagliptin On The Management Of Type 2 Diabetes

Diabetes is a growing concern and health challenge for the American people (b). Diabetes is a condition in which the body cannot react to insulin appropriately or either cannot produce insulin efficiently (w). “Without a properly functioning insulin signaling system, blood glucose levels become elevated and other metabolic abnormalities occur, leading to the development of serious, disabling complications” (w). There are numerous forms of diabetes amongst the nation, however, there are three main forms of diabetes. Most people have heard of type one diabetes, type two diabetes, and gestational diabetes because they are common. Type two diabetes deals with a resistance to insulin, while

Diabetes is a very common chronic medial disorder and expected to be a big medical challenge of the twenty first century (Clark, 2004). It is a condition, in which the glucose level in the blood becomes so high that the body is unable to utilize it properly. This long-term condition results when the pancreas of the victim is either not able to produce enough insulin (sometimes even cannot produce any insulin) or the insulin produced cannot work properly. Diabetes is divided into two main types: Type 1 and Type 2. Type 1, also known as insulin dependent diabetes milletus (Masharani, 2008) cannot be prevent while Type 2 can be prevented but if the patient is at pre-diabetes stage.

Considerable advances in the past treatment of type II diabetes include the application of lifestyle intervention and prevention efforts aimed at delaying development of glucose intolerance in order to evade diabetes and the progression of new curricula of glucose in the blood-lowering prescriptions to appendage current treatments (DeFronzo, 2010) (Mazzola, 2012). Presently, the control and maintenance of type II diabetes centres on control of glucose by the decrease of haemoglobin and glucose in the blood (DeFronzo, 2010). Current treatment strategies focus on the progression of therapeutic factors that affect the defects contributing to type II diabetes and thus, provide sustainable glucose control through a delaying of disease development

Incretins reduces gastric emptying and also inhibit glucagon release from the alpha-cells and improves the glycemic control alongside decreases the body weight and systolic blood pressure in type 2 diabetic patients [26]. Risk of hypoglycemia is low due glucose-dependent mechanism of action. Thus, incretin mimetics have become an important part for treating T2DM. Incretin based drugs include DPP-4 inhibitors and GLP-1 receptor agonists (Exenatide and Liraglutide).

For many type 2 diabetic patients, lifestyle modifications with a combination of metformin is not effective. For improved individualized HbA1c targets, a combination of metformin and a secondary therapy is recommended. (5) Although this therapy is recommended, many healthcare providers recommend patients to use a dual or triple oral therapy before choosing to use injectable basal insulin and a GLP-1 in order to reach the desired individualized targets.

Type 2 diabetes mellitus is often treated with metformin and an oral hypoglycemic agent (e.g. sulfonylurea); however, if this combination is not effective, insulin is often added to replace the oral hypoglycemic agent for better blood sugar control. In type 1 diabetes, intensive insulin therapy is designed to mimic normal insulin secretion as closely as possible.1 While the

Type 2 diabetes results from a multitude of defects: impaired insulin secretion, insulin resistance, and defects in GLP-1 secretion and action. Prior to the onset and throughout the course of the disease, beta cell function and pancreatic mass deteriorate; causes may be lipotoxicity, glucose toxicity, increased age, genetics, insulin resistance, and incretin deficiency. Insulin resistance takes place in the liver, adipose, and skeletal tissues (1), ultimately leading to decreased peripheral uptake and hyperglycemia. In the liver, lack of insulin action results in gluconeogenesis and glycogenolysis, further potentiating the hyperglycemia. In fat cells, decreased GLUT4 leads to excessive release of free fatty acids and adipocytokines (2). Because

Semaglutide is a glucagon-like peptide-1 (GLP-1) agonist, which is a new antidiabetic drug that has been studied to show therapeutic benefits in non-insulin dependent diabetics and in patients with preexisted heart disease. Type 2 diabetes often leads to cardiovascular complications especially atherosclerosis which can lead to a myocardial infarction. GLP-1 receptors are widely presented in different tissues including the cardiovascular and pancreatic tissues. GLP-1 agonist performs many functions including stimulating pancreatic beta-cells to release insulin, suppressing glucagon secretion, promoting blood glucose balance, delaying gastric emptying, and decreasing appetite. Excess sugar in the blood can prevent glucose absorption into cells

The management of diabetes mellitus (DM) is to eradicate symptoms and to minimize the development of complications (Khardori, 2014).The minimization of microvascular damages involving kidney and eyes can accomplished through managing glycemia and blood pressure (BP) (Khardori, 2014). The minimization of macrovascular damages, for examples: coronary, cerebrovascular, peripheral vascular, can be achieved by active control of lipids and hypertension (HTN), anticoagulant therapy, and glycemic control. The DM patient should maintain their glucose level close to near-normal levels of 90 to130 mg/dL and hemoglobin A1C (HbA1c) levels below 7% (Khardori, 2014). HbA1c should be evaluated every three to six months (Khardori, 2014).The DM patient’s BP should be maintained below 130/80 mm Hg, and even lower for the patient’s with DM nephropathy (Khardori, 2014). Low-density lipoprotein (LDL) goal of less than 70 mg/dL in patients with preexisting cardiovascular disease (CVD) or patients with the risk factors for coronary vascular disease (CVD) (Domino & Baldor, 2013).

The DPP 4 inhibitors come in the class of incretin based therapies for type 2 diabetes. The incretin effect is generally blunted in type 2 diabetes patients.16 The two main incretin hormones responsible for blood glucose regulation are GLP-1 (glucagon like peptide-1) and GIP ( glucose dependent insulinotropic peptide). These two hormones are secreted when carbohydrates and fats are consumed and they result in increased glucose dependent insulin secretion or postprandial insulin release and decreased glucagon secretion. Both of these hormones tend to be rapidly metabolized in the circulation by the enzyme DPP 4 (dipeptidyl peptidase). Type 2 diabetes mellitus is characterized by decreased insulin sensitivity and progressive loss of pancreatic beta cell insulin secretion .The DPP 4 inhibitors block the breakdown of naturally occurring GLP 1 by competitively inhibiting the binding of GLP 1 to DPP .The DPP 4 inhibitors decrease the acitivity of the enzyme dipeptidyl peptidase by greater than 80% for up to 24 hours, thereby augmenting the meal related circulating concentrations of both GLP-1 and GIP.19The duration of effect of GLP 1 is thereby increased, thus resulting in a reduction in hepatic glucose output and increase in insulin production.

The synthetic preparation 'Exenatide ' targets the GLP-1 receptor (GLP-1R) and acts as an agonist which elicits action of the GLP-1 pathway while displaying other antihyperglycemic actions (McDougal, McKay & Fisher 2011). Reactions of an active GLP-1 pathway typically lead to insulin secretion by the beta cells and the suppression of inadvertently elevated glucagon secretion (Iltz, 2006). The Active Pharmaceutical Ingredient (API), has been proven clinically to elicit favourable responses on patient; glucose-dependent insulin secretion, first-phase insulin response, glucagon secretion, gastric emptying and food intake (Derosa et.al, 2010). Exenatide preparations are made by incorporating molecules into a matrix of poly-D, L-lactide-co-glycolide which, although similar to the native glucagon-like peptide has a much longer duration of action (Kalra 2013).

I have chosen the above topic because the guidelines are very vague in recommending this combination therapy even though we have clear cut guidelines recommending the use of individual agents in the treatment in Type II Diabetes patients. American diabetes association (1) guidelines recommend advising lifestyle modifications like healthy eating, increased physical activity and weight control, and if the patient fails to meet the target HbA1C levels on lifestyle changes, Metformin is added and over a period of three months, if the patient does not reach the target A1C levels, patient can be started on two drug combinations and we have several options to do this, from sulfonylureas, TZDs ,GLP-1 Analogues, DPP-4 inhibitors and insulin. A search of literature for this combination (2) shows that there are very few clinical studies conducted with the combination of GLP 1 analogues and Insulin and in these studies it was more common to find short-acting GLP-1 RA (exenatide twice daily, liraglutide once daily, lixesanatide once daily) treatment added to an existing insulin regimen (with or without concomitant OAMs) rather than insulin added to existing GLP-1 RA therapy.

In the brain, GLP-1 increases satiety and neuroprotection while decreasing appetite. In the pancreas, aside from insulin secretion, in β cells it causes and increase in glucose sensitivity, neogenesis, and proliferation while increasing insulin expression and decreasing glucagon release. In bones, GLP-1 increases bone formation while decreasing bone resorption. In the heart, it offers glucose uptake, cardioprotection and increases cardiac function. The function of GLP-1 on the stomach has implications that it could be used as a treatment for T2DM as well as obesity. Since GLP-1 has a tendency to decrease gastric emptying, secretion, and motility, this will in part also slow down the release of glucose into the bloodstream making GLP-1 a target for treatment in

The pathophysiology of type 2 diabetes mellitus (T2DM) is complex and varied. The core defects of T2DM include quantitative and qualitative β-cell dysfunction, peripheral (skeletal muscle) insulin resistance, and elevated glucose production in the liver, as well as increased lipolysis when obesity is present. However, it is now being recognized that other known mechanisms, including increased glucagon, decreased incretin effect, increased glucose reabsorption in the kidneys and some neurotransmitter dysfunction, are also involved in the pathophysiology of T2DM1. The currently available antidiabetic agents have been developed to target one or more of the underlying defects or processes involved in T2DM2. Normally, glycemic control in patients

Diabetes is a systemic disease caused by a decrease in the secretion of insulin or reduced sensitivity or responsiveness to insulin by target tissue. (Beale, et al., 2011) The incidence of diabetes is growing rapidly in the United States and worldwide. An estimated 347 million people around the world are afflicted with diabetes. (Whalen, et al., 2012) According to World Health Organization (WHO), Diabetes prevalence among adults over 18 years of age has risen from 4.7% in 1980 to 8.5% in 2014. It is the major cause of blindness, kidney failure, heart attack, stroke and limbic amputation. World Health Organization (WHO) projects that diabetes will be the 7th leading cause of death in 2030. It is a complex and costly disease that can affect nearly every organ in the body and result in devastating consequences. The leading cause of non-traumatic lower extremity amputations, renal failure, and blindness in working-age adults, diabetes is also a major cause of premature mortality, stroke, cardiovascular disease, peripheral vascular disease, congenital malformations, perinatal mortality, and disability. (Cefalu, 2000) Insulin therapy and oral hypoglycemic agents have demonstrated improvement in glycaemic control. However, Insulin therapy has some disadvantages such as ineffectiveness following oral administration, short shelf life, of the need for constant refrigeration, and fatal hypoglycaemia, in the event of excess dosage.