Combination Drugs for Type 2 Diabetes

Introduction

The key factors to promote and maintain good health throughout the life are diet and nutrition. Chronic diseases that are related to imbalance in the diet and nutrition are diabetes mellitus, cardiovascular disease, stroke, obesity, cancer, osteoporosis and dental diseases [1, 2]. In 2001, 60% of the total deaths among 56.5 million people is mainly due to chronic diseases contributed approximately 46% of the global burden of disease [3]. The global burden of chronic diseases is expected to increase to 57% by 2020. The incidence of chronic disease is high in developing countries like India when compared to developed countries.

It has been projected that, by 2025, chronic disease like Diabetes Mellitus will account for almost three-quarters of all deaths, and 70% of deaths due to diabetes will occur in developing countries [4,5,6].

Diabetes mellitus (DM) is a metabolic disorder characterized by hyperglycemia which is mainly due to the disturbances in carbohydrate, protein and fat metabolism leading to the dysfunction and failure of various organs [7]. Signs and symptoms of Diabetes mellitus include:

• Polyuria
• polydipsia
• polyphagia
• blurring vision and
• weight loss [8].

It was predicted that India has 65.1 million adult diabetes mellitus patients by the year 2015 carrying 2nd position among the top 10 countries with high number of diabetes mellitus and this number is expected to increase up to 109 million by 2035[9]. Based on the etiology, WHO has classified DM as TYPE1 DIABETES MELLITUS (insulin dependent diabetes mellitus)and TYPE2 DIABETES MELLITUS (Non insulin dependent diabetes mellitus)[10]. However these classification has disappeared , and new classification has been proposed which explains four types of DM :TYPE I, TYPE II , other specific types and gestational diabetes[11].

Get quality help now

Doctor Jennifer

Verified

Proficient in: Diabetes

5 (893)

“ Thank you so much for accepting my assignment the night before it was due. I look forward to working with you moving forward ”

+84 relevant experts are online

Hire writer

Type1 DM mainly targets pancreatic beta cells by the invasion of mononuclear cells into the islets of pancreas. This inflammatory reaction can be termed as insulitis, death of beta cells in the period of insulitis is mainly due to direct contact with macrophages and T cells which may cause initial loss of first phase insulin secretion to glucose [12,13].

Diabetes mellitus type I:

The major cause of type I DM includes

• Dietary factors,
• Genetics,
• Anti and perinatal risk factors,
• Stress full life events and
• Environmental risk factors[14].

As Type 1 DM is mainly due to insulin deficiency, rapid acting insulin can be used when the patient requires rapid onset and short duration, and the clinical presentation of type 1 DM include polyuria, hyperglycemia, polyphasia, polydypsia.[15].

Diabetes mellitus type II:

Type II DM is a chronic metabolic disorder which is otherwise called as Non insulin dependent diabetes mellitus (NIDDM). Type 2 DM is characterized by insulin resistance and its deficiency, hyperglycemia. Despite of adequate production of insulin, the cells do not have the ability to uptake that insulin due to the resistance. The major causes of type 2 DM includes:

• Genetic,environmental and behavioural ,
• lifestyle factors:
• sedentary life style ,
• smoking,
• physical inactivity ,
• increased consumption of alcohol , and
• Overweight may have the high chances of getting type 2 DM[16,17].

Pharmacologic therapy of type II diabetes has changed dramatically in the last 10 years, with better drugs and drug classes becoming available. These drugs allow practicing combination oral therapy, often with enhanced glycemic control that was previously beyond the reach of medical therapy [18].

Different Agents used in treating diabetes mellitus include the following:

• Biguanides
• Sulfonylureas
• Meglitinide derivatives
• Alpha-glucosidase inhibitors
• Thiazolidinediones (TZDs)
• Glucagonlike peptide–1 (GLP-1) agonists
• Dipeptidyl peptidase IV (DPP-4) Inhibitors
• Selective sodium-glucose transporter-2 (SGLT-2) inhibitors
• Insulins
• Amylinomimetics[19]

Traditionally, diet modification has been the cornerstone of diabetes management. By modifying the diet, Weight loss is more likely to control glycemia in patients with recent onset of the disease than in patients who are significantly insulinopenic [20]. Medications that induce weight loss, may be effective in highly selected patients but are not generally indicated in the treatment of the average patient with type 2 diabetes mellitus[21].

Patients who are symptomatic to pre diabetes may require transient treatment with insulin to reduce glucose toxicity (which may reduce beta-cell insulin secretion and worsen insulin resistance) or an insulin secretagogue to rapidly relieve symptoms such as polyuria and polydipsia.[22]. Major factor in selecting a class of drugs, or a specific medication within a class, to initiate therapy or when changing therapy, is the ambient level of glycemic control when glycemic levels are closer to the target levels (e.g., HbA1C 8.5%), classes with greater and more rapid glucose-lowering effectiveness, or potentially earlier initiation of combination therapy, are recommended [25]

Biguanide

Metformin is one of the primary choices of drugs widely used for the treatment of type II diabetes mellitus among biguanides class if the patient is obese. Although this biguanide derivative has been used for more than 50 years, mechanism of action of metformin includes  decrease of glucose absorption in the small intestine, increase of glucose transport into cells, decrease in the plasma free fatty acid concentrations and inhibition of gluconeogenesis [26]. The pleiotropic actions of metformin include impact on plasma lipid profile, decrease of oxidative stress, and increase in plasma fibrinolytic activity. Although metformin is not metabolized, the latest research has shown that it is actively transported into hepatocytes and renal tubular epithelium, by OCT1 (organic cation transporter 1, encoded by the SLC22A1 gene) and OCT2 (organic cation transporter 2, encoded by the SLC22A2 gene), respectively. However, MATE1 transporter (multidrug and toxin extrusion 1 protein) is encoded by the SLC47A1 gene and facilitates metformin excretion from these cells into bile and urine [27, 28]

Sulfonyl ureas

They are traditionally classified into 2 groups (or generations). First-generation drugs such as tolbutamide and chlorpropamide are no longer used. Second generation sulfonylureas include Gliclazide, glipizide, glibenclamide and glimepiride being currently used. While Second-generation drugs are equally effective in lowering blood glucose concentrations, but there are differences in absorption, metabolism and dosing differences when compared to the first generation [29]. Sulfonylureas should be considered for diabetic patients who are either not obese or those for whom metformin is contraindicated or is not enough to achieve adequate glycemic control. The primary pharmacological response of sulfonylureas is to rise the plasma insulin concentrations; consequently they are effective only when residual pancreatic β-cells are present.

The rise in plasma insulin levels occurs for two reasons [30]. Firstly, there is stimulation of insulin secretion by pancreatic β-cells, and secondly, there is a decrease in hepatic clearance of insulin. In particular, the latter effect appears mainly once the rate of insulin secretion is enhanced. In fact, in the first month of treatment, the levels of insulin and insulin response to glucose rise rapidly, resulting in lowered blood glucose [31]. After this period, baseline and stimulated insulin levels become lower compared to those measured at the beginning of treatment; They act by binding to the specific receptor for sulfonylureas on β-pancreatic cells, blocking the inflow of potassium (K+) through the ATP- dependent channel: the flow of K+ within the β-cell goes to zero, the cell membrane becomes depolarized, thus removing the electric screen which prevents the diffusion of calcium into the cytosol [32].

Alpha glucosidase inhibitors

(Acarbose and voglibose). Alpha-glucosidase inhibitors (AGIs) are drugs that inhibit the absorption of carbohydrates from the gut and may be used in the treatment of patients with type II diabetes or impaired glucose tolerance (IGT). There is currently no evidence that AGIs are beneficial to prevent or delay mortality or micro- or macro vascular complications in type 2 diabetes. Its beneficial effects on glycated hemoglobin are comparable to metformin or thiazolidinediones, and probably slightly inferior to sulphonylurea [33].

AGIs reversibly inhibit a number of alpha-glucosidase enzymes (eg, maltase), consequently delaying the absorption of sugars from the gut.In a recent study among healthy subjects it was suggested that the therapeutic effects of AGIs are not only based on a delayed digestion of complex carbohydrates, but also on metabolic effects of colonic starch fermentation[34,35]. Initially, oral metformin monotherapy plus lifestyle interventions may be successful in controlling the symptoms of type 2 diabetes, but 5-10% of patients per year subsequently fail to maintain target HbA1c levels . In a prospective study of patients with newly diagnosed type 2 diabetes , randomised to lifestyle modification alone or lifestyle modification plus either a sulfonylurea, metformin or insulin therapy, 50% of patients receiving monotherapy required the addition of a second drug after 3 years; and by 9 years, 75% needed multiple therapies to achieve target HbA1c levels [36] .

Metformin provides reduction of body weight and ameliorates lipid abnormalities in obese and non-obese patients. Moreover, metformin is effective in reducing C reactive protein (PCR) and lipoprotein a (Lp(a)) in thus improving, at the same time, endothelial dysfunction . If metformin is not tolerated or contraindicated, the second choice is represented by a thiazolidinedione (TZD) or a sulfonylurea (SU). Sulfonylureas are efficacious and particularly useful in type 2 diabetic patients who present primarily insulin secretion deficiency and, in association with insulin sensitizing drugs (metformin and TZD), in those patients with type 2 diabetes mellitus who do not achieve recommended glycemic control [37].

Evidences are available concerning with a potential risk of cardiovascular mortality in subjects treated with metformin in association with SUs. In the UKPDS a significant increase in mortality was observed in those patients in whom metformin was added to initial SU treatment [38]. Other evidences point out a potential risk in adding metformin to SUs therapy in patients with chronic heart disease (CHD). A theoretical cardiac risk for first generation SU has been observed. Latest sulfonylureas, glimepiride, gliclazide and glipizide have lower affinity for cardiac SUR-receptors [39].

Glimepiride plus metformin

Glimepiride and metformin are the most common and widely used oral hypoglycemic agents in the world. Metformin improves insulin resistance, and is recommended as the first choice medication for newly diagnosed type II diabetes patients as per numerous standard guidelines. Glimepiride is a third generation sulfonylurea that stimulates insulin secretion. Unlike conventional sulfonylurea, glimepiride has high selectivity toward the pancreatic ATP-sensitive potassium channel , increases glucose transport, and shows various extrapancreatic effects in muscle and fat cells[40]. For these benefits, glimepiride is prescribed as a primary monotherapy or additional medication when metformin monotherapy has failed.

Most existing studies have been carried out for patients who have uncontrolled blood glucose levels, even after using metformin at the maximum dose or higher [41]. The combination therapy with metformin and glimepiride showed superior efficacy than metformin or glimepiride monotherapy in type II diabetes patients who had failed glucose control with metformin 2,550 mg. However, metformin shows a dose-dependent blood glucose lowering effect only up to 1,500 mg, and the dose above that shows no significant additional response [42]. Due to the adverse effects associated with the use of SU, combinatorial therapy has been focused mainly on adding metformin drug.

Metformin and sulfonylurea combinatorial therapy is associated with reduced mortality. Combining both these drugs at an early stage that act by different individual mechanisms has an advantage of improving glycemic control effectively. This has the potential advantage of increasing the therapeutic effectiveness of both these agents and decreasing the side effects if lower doses could be used [43].