Metformin Combinatorial Therapy for Type 2 Diabetes Mellitus Keerthi Kupsal 1 , Saraswati Mudigonda 1 , Nyayapathi VBK Sai 2 , Krishnaveni Neelala 2 and Surekha Rani Hanumanth 1* 1 Department of Genetics, University College of Science, Osmania University, Telangana, Hyderabad-500007, India 2 Department of Cardiology, South Central Railway Hospital, Lallaguda-500013, Secunderabad, India * Corresponding author: Dr. Surekha Rani Hanumanth, M.Sc, PhD, Assistant Professor, Department of Genetics, Osmania University, Hyderabad-500007, Telangana State, India, Tel: +919866620067; Fax: +91-4027095178; E-mail: surekharanih@gmail.com Received date: Jul 01, 2016; Accepted date: Jul 27, 2016; Published date: Aug 03, 2016 Copyright: © 2016 Kupsal K, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abstract Type 2 Diabetes mellitus (T2D) is a worldwide chronic epidemic with increasing incidence. The current algorithm for medical management of type 2 diabetes includes the pharmacological treatment with nine classes of anti-diabetic drugs. Among the nine classes of drugs approved, metformin, an oral hypoglycemic agent from the biguanide family is widely prescribed as the first-line anti-diabetic monotherapy for the treatment of initially diagnosed T2D individuals. The failure of monotherapy to achieve sustain glycemic control prompted the early use of aggressive combination therapies with other anti-diabetic drugs. The primary aim of T2D treatment is to achieve target glycemic control and reducing further complications of diabetes. Hence, fixed dose combination drugs are preferable in order to reduce pill burden and capital investment. Single pill combinations containing drugs for two different diseases can also be prescribed for avoiding extra medication and to reduce further diabetic complications. Our review addresses the mode of action of anti-diabetic drugs and their combinatorial therapy with metformin. Keywords: Type 2 Diabetes mellitus; Metformin; Anti-diabetic drugs; Combinatorial therapy; Fixed dose combination drugs Introduction Type 2 diabetes mellitus (T2D) is a global public health crisis worldwide, facing escalating epidemic particularly in developing countries. It is one of the most challenging health problems and insidious disease in the 21 st century. India is a repository to nearly 62 million diabetics making the world’s highest diabetes burden country being termed as the ‘diabetes capital of the world’. Te number of diabetic patients is set to increase to 69.9 million by the year 2025. India’s diabetes numbers are expected to cross the 100 million mark by 2030 [1]. T2D is a disastrous disorder characterised by hyperglycemia as a result of insulin resistance, impaired insulin secretion or both. Te pharmacological treatment of T2D include eight classes of approved oral anti-diabetic drugs (biguanides, sulfonylureas, thiazolidinediones, glinides, alpha-glucosidase inhibitors, amylin mimetics, glucagon-like peptide 1 mimetics and dipeptidyl peptidase 4 inhibitors). Insulin therapy is recommended for patients with initial HbA1c level greater than 9%. Over 120 million people worldwide are prescribed metformin, a sole member of biguanide family drug as the frst line oral anti-diabetic therapy owing to its safety profle and reduced risk of side efects. It has an exceptional therapeutic index for diabetes to treat hyperglycemia. It is considered as the gold standard anti-diabetic drug due to the insignifcant risk of hypoglycemia and prescribed as frst-line monotherapy. When metformin monotherapy fails to achieve the recommended standards of care like uncontrolled hyperglycemia, combinatorial therapy with one or two other anti-diabetic drugs along with ongoing metformin therapy is prescribed for efective glycemic control. Use of metformin is efective in lowering glycosylated haemoglobin (HbA1c) by 1 to 2 percentage points when used as monotherapy or in combination with other anti-diabetic drugs [2]. Substantial evidence indicates that combinatorial therapy can establish superior glycemic control in most of the patients and targets key pathophysiological defects and help to achieve recommended targets in diabetes management. Nine classes of anti-diabetic drugs, their mechanism of action, rationale of combinatorial therapy and the list of combination drugs available in the market are discussed in Tables 1-3. Metformin - Mode of action Metformin from the biguanides family is an antihyperglycemic agent and is the drug of frst choice to treat initially afected type 2 diabetic cases. It is a safer drug with multiple physiological and molecular efects associated with minimal toxicity. Metformin lowers hyperglycemia by reducing glucose absorption in intestine, increases glucose uptake in peripheral tissues and stimulates insulin secretion from pancreatic beta-cells. Metformin acutely decreases hepatic glucose output by increasing insulin suppression of gluconeogenesis and reducing the energy supply through activation of AMP-activated protein kinase (AMPK) by inhibition of mitochondrial respiratory-chain complex 1 and consequent increase in NADH oxidation and ultimate reduction in synthesis of ATP (Figure 1). Tis mechanism induces glucose uptake into muscle cells, thus lowers the fasting blood glucose in T2D patients [3], (Figure 2). Metformin also regulates its efect in the indirect inhibition of insulin receptor expression and tyrosine kinase activity, thereby enhancing insulin sensitivity and reducing insulin resistance in diabetic patients [4,5]. Kupsal, et al., J Metabolic Synd 2016, 5:3 DOI: 10.4172/ 2167-0943.1000210 Review Article Open Access J Metabolic Synd, an open access journal ISSN:2167-0943 Volume 5 • Issue 3 • 1000210 Journal of Metabolic Syndrome J o u r n a l o f M e t a b o l i c S y n d r o m e ISSN: 2167-0943