INTRODUCTION:

Diabetes mellitus is a chronic disease caused by inherited and acquired deficiency in the production of insulin by the pancreas, or by the ineffective action of insulin produced. This deficiency in the production of insulin by the pancreas results in an increase in the concentrations of glucose in the blood. This insulin deficiency risks the damage to several body systems such as the blood vessels and nerves.¹ The sign and symptoms of diabetes mellitus include weight loss, polyuria, polyphagia, polydipsia, blurring of vision. The increased blood glucose level in diabetes mellitus leads

to long-term damage and dysfunction to many body organs. It causes complications in the heart which may lead to various cardiovascular disorders. In some patients, it may lead to ocular damage, leading to blindness as in the case of (diabetic retinopathy). In addition to that, DM also affect the kidneys, which may lead to kidney failure as in the case of diabetic nephropathy ^2,3. The known types of DM are type 1 and type 2. Type 1 diabetes is an autoimmune disorder; the body immune system attacks its insulin-producing beta cells which produce insulin rendering them inactive. Indeed, type 2 diabetes ensues due to less insulin produced by the beta cells in the pancreas or resistance to the effective action of this insulin ^{4, 5}.

There were close to 400 million diabetic people in 2013, and the number is expected to increase to 592 million in the next two decades. Worldwide prevalence in all age group is estimated to almost double from the year 2000 to 2030. ‘Type 2’ diabetes is present in 90% of diabetes patients while ’Type 1’ diabetes makes around 10% of the total cases of diabetes ^{4, 6}. This increase in number type 2 diabetes patients would be owing to the causes such as population growth, urbanization, and aging of population and change of lifestyle. The documented t ranking for the number of people living with diabetes mellitus proved highest in China followed by India ⁷. However, India was once known to be the diabetes capital of the world. India had about 61.3 million people living with type 2 diabetes mellitus in 2011. It has been predicted to increase to 101.2 million by the year 2030 ⁸. This review explores diabetes mellitus, its non-pharmacological and pharmacological therapy. It also highlights updates on combination therapy of DM and how fundamental it is in the management process.

Pathophysiology:

The insulin dependent diabetes mellitus (IDDM), which is similarly known as type 1 diabetes, occurs as a result of autoimmune destruction of the pancreatic beta cells resulting in the reduction of the insulin secretion or total deficiency in the insulin secretion. The insulin dependent diabetes mellitus (IDDM), which is similarly known as type 1 diabetes, occurs as a result of autoimmune destruction of the pancreatic beta cells resulting in the reduction of the insulin secretion or total deficiency in the insulin secretion. IDDM occurs mainly in children between 12-15 years of age and accounts for about 10 - 20% of the known diabetes⁵. In type 1 diabetes mellitus, 90% of beta cells get destroyed before the clinical manifestations of diabetes symptoms. Therefore lack of insulin in type1 of diabetes mellitus, which leads to different physiological malfunctions such as uncontrolled lipolysis, an elevated level of free fatty acids in the blood, and this suppresses the metabolism of glucose in peripheral tissues like the skeletal muscle⁶. Eventually, the pancreas fails to secrete insulin in response to glucose ingestion in IDDM thus need for insulin required at all times.

Additionally, the pancreatic alpha cells also function abnormally by the secretion of excess glucagon in this type of diabetes mellitus9. Glucagon is not suppressed by hyperglycemia in type 1 diabetes mellitus. This lead to an increase of glucagon levels⁵. The non-insulin dependent diabetes mellitus (NIDDM), which is also known as, type 2 diabetes is estimated to be 80-90% of diabetic cases. It occurs in the adult of 35 years and above most common in obese people ⁷. Obesity act on the diabetogenic factor in a genetically predisposed person by increasing insulin resistance which in turn, lessens the insulin disposal on the insulin receptors of the target cell¹⁰. Insulin resistance, as well as deficiency, is common in the average NIDDM.

There several factors which can directly or indirectly relates to type 2 diabetes mellitus which comprises of genetic factors, impaired insulin secretion, insulin resistance, poor eating habit, obesity, stress, lack of exercise, smoking, and alcohol consumption¹¹. The decrease in glucose responsiveness occurs before the clinical manifestation of the disease⁵.

Complications of diabetes mellitus

Glucose is an essential molecule in human life more specifically for the proper function of the nervous system thus managing the glucose concentration is an important; since it has a powerful adverse effect of both hypoglycemia and hyperglycemia. However, maintaining the glucose level within the narrow window is essential to avoid the complications¹². Chronic diabetes mellitus has long-term damaging effect leading to failure and dysfunction of different organs such as the heart, blood vessels, eyes, kidney, and the nerves.

Cardiovascular disorders are the frontline cause of mortality in type two diabetic patients. Diabetic retinopathy results in blindness, diabetic neuropathy causes nerve damage and kidney failure. Many patients received renal replacement primarily due to diabetic nepropathy¹³.One of the past literature studies reveals chronic hyperglycemia of diabetes mellitus which has a long-term damaging effect on organs especially; the heart, blood vessels, eyes, kidney, and the nerves causes failure and dysfunction. A systematic review of population studies evidences the risk of dementia increases in patients with diabetes mellitus¹⁴.

About 20-50% of patients diagnosed with type 2 diabetes present with microvascular complications or macrovascular complications¹⁵. Improving patients lifestyle, continual medication, and health education are useful in the prevention and reduction of diabetic complications ³.

Dietary management of diabetes mellitus

Dietary modification alongside lifestyle changes in regards to the management of type 2 diabetes mellitus must always go along with medication use. Various new findings suggest a positive correlation between declines in the progress of type two diabetes mellitus and a healthy diet tailored to meet the needs of the disease^{16, 17}. On a macronutrient level, carbohydrates have more effect on glucose levels, but studies show that protein, as well as fat, directly and indirectly, play a role in diabetes^18,
19. The glycaemic index (GI) measures the speed and quantity at which level food raises blood glucose Carbohydrate-containing foods are of two types, the food with high and low glycaemic index.

The former not only increases blood glucose rapidly but also speeds up the insulin responses after consumption. The foods with a low glycaemic index such as wholegrain bread, oats, and lentils, usually contain carbohydrates which slowly break down during digestion and gradually assimilate. Therefore, these foods have a lower effect on blood glucose levels and insulin response. A recent review shows that “low-GI diet is more effective in controlling glycated hemoglobin and fasting blood glucose levels compared to a higher-GI diet in controlled patients with type 2 diabetes”²⁰. Another study in Canada found that low-fiber diet decreased Haemoglobin' (HbA1c); blood glucose levels and increased high-density lipoprotein cholesterol levels compared with the high-fiber diet²¹. Protein is said to have minimal effect on blood glucose levels. However, slightly higher protein intake 20–30% of the total energy of both animal and plant protein may be beneficial for older adults, obese and hyperglycemic patients²². According to the American Diabetes Association, the recommendation for protein intake depends on individuals. Other health issues such as the extent of glycaemic control, the presence of kidney disease, obesity, and the age of the patient are considered²³.

Obesity is a common risk factor for the development of type 2 diabetes mellitus²⁴. Indeed, it needs to targeting therapy for diabetic individuals to lose weight. Food low in fat is encouraged for patients with diabetes. Good fats are those which monounsaturates fatty acid, (MUFA), which are rich in olive oil, canola oil, avocados; and polyunsaturation fatty acid (PUFA) which include omega-6 and omega-3 fatty acids, also rich in corn oil, sunflower oil, wild salmon, Alaskan halibut, tuna, and sardines²⁵. A study showed that replacing bad fats found in red meats and butter with food rich in MUFA and PUFA should be encouraged to increase the sensitivity of insulin and reduce the risk of DM²⁶. Such composition of the diet may lower the risk of a cardiovascular disorder by reducing the level of serum triglycerides²⁷. Lifestyle changes can evidence through regular physical activity is a way to manage type 2 diabetes mellitus²⁸.

Regular physical activity such as walking and exercises helps; to lose weight, improves blood cholesterol levels, and so lowers the blood glucose levels, and blood pressure. Exercise also improves the low-density lipoprotein ratio (LDL) to high-density lipoprotein cholesterol (HDL). This decreases triglycerides level in the blood²⁹.

Pharmacological management of diabetes mellitus

Pharmacological management involves the use of drugs for patients in diabetes management. The drug treatment can be given alone or in combination which depends on patients need. Insulin is the paramount and first treatment for diabetes mellitus. It was first discovered and tested on humans in the 19^th century³⁰. Insulin operates by improving glucose metabolism. Currently, consider the most effective treatment for hyperglycemia. There is no upper limit in the dose given for diabetes therapy; so it can be used to reduce any elevated hemoglobin (HbA1c) level. It also reduces triglycerides and increases HDL³¹. Initially, insulin resistance was a treatment for patients with type 2 diabetes. Nowadays, it is also known to be present in type 1 diabetes mellitus patients. Use of insulin can bed both former and later³². Different types of insulin include the rapid-acting drugs, i.e., Novolog, Humalog and Apidra, short-acting drug, i.e., Humulin R and Novolin R, intermediate-acting insulin NPH, long-acting basal drug, i.e., Lantus, Levemir and Tresiba, and premixed insulin such as Humalog and Novolog mix at different ratios ³⁰.Pharmacologically, the appropriate and effective therapy bases on whether the patient is deficient of insulin, resistant to insulin, or even both. Treatment options include the use of insulin sensitizers. They reduce the glycemic load by enhancing the insulin actions in peripheral tissues³⁰. The most important class is the biguanide, i.e., metformin and thiazolidinediones. Metformin products, approved in the 1950s, suppress the hepatic glucose output. It is the long-acting drug enhancing the sensitivity of insulin in the fat and muscles and lowering the fasting glycaemia³³. It does not cause hypoglycemia when used as a single dose of monotherapy. It can lead to a decrease in plasma lipid leading to weight loss³⁴. It can lead to decrease in plasma lipid thereby leading to weight loss³⁴. Literature reveals Thiazolidinedione’s are agonists of peroxisome proliferator-activated receptor gamma.

They act in a similar pattern as metformin. Thiazolidinediones, marketed as rosiglitazone and pioglitazone, thiazolidinediones, may cause increase subcutaneous fluid retention as well as weight gain. Insulin secretagogues such as sulfonylureas and glinides act by stimulating the secretion of insulin from the pancreas³⁵. The action augments glucose uptake by the fat and muscles. Sulfonylurea can be used either as monotherapy or as an adjunct to metformin. They have low cost and extensive clinical experience³⁵. Some of the adverse effects of sulfonylurea include hypoglycemia and weight gain. Some of the hypoglycemia episodes, which include seizures and coma, can be clinically significant, especially in elderly patients⁶. The glinides act in the same way as the sulfonylurea; however, they act faster and have a shorter half-life.

Another class of antidiabetic therapy is incretin-based therapies for type 2 diabetes. They are available in the form of oral and injectable formulations. They are glucagon-like peptide-1 [GLP-1]) receptor agonists and dipeptidyl peptide - 4 [DPP-4]) inhibitors. Incretin-based on medications which increase the risk of acute pancreatitis in patients; DPP-4 inhibitors market saxagliptin, sitagliptin, vildagliptin, and linagliptin. These are a compound that also acts by inhibiting the enzymes DPP-4 which inactivate glucagon-like peptide-1, GLP-136, and glucose-dependent insulinotropic peptide GIP36. GIP and GLP-1 lower blood glucose level by increasing insulin secretion, and decreasing the release of glucagon^{37, 38}.

The United States Food Administration (FDA) warned sitagliptin, saxagliptin, linagliptin, alogliptin may cause joint pain that can be severe and disabling³⁹. They are also associated with suppressing of the patient’s appetite. The US FDA approved a synthetic form of amylin called pramlintide. It is a hormone co-secreted with insulin by beta cells of the pancreas. It acts by slowing gastric emptying, suppressing the secretion of glucagon, and suppressing patient’s appetite through central pathways. Literature studies reveal pramlintide acts primarily on postprandial blood glucose levels. Its main side effects include nausea and hypoglycemiam^{40, 41}. Sodium-glucose co-transporter - 2 inhibitors, (SGLT2) inhibitors are the newest class of antidiabetic medications, e.g., empagliflozin, dapagliflozin, remogliflozin. They were recently using the treatment of type 2 diabetes mellitus. They act by increasing urinary glucose excretion; thereby decrease plasma glucose level. SGLT2 inhibitors improve insulin resistance and decrease glycated hemoglobin⁴². The United States food and drug administration (FDA) warned the canagliflozin, empagliflozin, and dapagliflozin may lead to ketoacidosis; this condition the body produces a higher level of blood acid called ketoacid which may lead to the hospitalization of patients³⁹.

COMBINATION THERAPY

For the past decade, the fixed-dose combinations (FDCs) therapy of orally administered drugs had been introduced for the management of different types of complications and diseases including tuberculosis, hypertension, HIV, and diabetes mellitus as well. Each dose usually consists of two or more pharmaceutical compounds in a single tablet. Fixed-dose combination is a substitute for individual medications that are dispensed separately (Loose-pill combination). Significance of FDCs has reasons such as simplifying the doses and timing the schedules for various medications. This helps reduce the frequency of omission and improve patient compliance.

This measure can help to reduce the frequency of omission of medicine and improve patient compliance. Additionally, greater efficacy can be attained with the combination of the lower doses of two agents when compared to loose pill combination^{43, 44}. Combining lower dose of glycaemic agents reduces the risk of an adverse event that more likely to occur in mono-therapy⁴⁵. FDCs FDCs are less expensive than loose-pills therefore, offers a financial advantage for patients. The type 2 diabetic patients, who use combination therapy, have greater adherence than those with the fixed combination therapy⁴⁵. Fixed-dose of combinations of antidiabetic agents is gradually becoming the treatment of choice for type 2 diabetes. Economically administration and compliance problem can be solved utilizing FDCs in patients with polypharmacy⁴⁶.

Recently, United States food and drug administration had approved synjardy tablet, which is the combination of (empagliflozin, metformin hydrochloride) used to treat type 2 diabetes mellitus. Glyxambiin a combination of Empagliflozin, and Linagliptin is approved. Empagliflozin sodium glucose co-transporter lowers blood glucose level by excreting the excess blood glucose into the urine. Table 1 depicts some available combination therapies marketed to achieve the benefit of FDCs.

Table 1: Selected marketed antidiabetic combination therapy

	Name of the Drugs	Composition	Indication
1	Glucovance	Metformin + glyburide	Type 2 diabetes
2	Actoplus Met	Metformin + Pioglitazone	Type 2 diabetes
3	Juvisync	Sitagliptin + Simvastatin	Type2 diabetes
4	Invokamet	Metformin + canagliflozin	Type 2 diabetes
5	Xigduo XR	Metformin + Dapagliflozin	Type 2 diabetes
6	Kombiglyze XR	Sexagliptin + Metformin	Type 2 diabetes
7	Duetact	Pioglitazon + Glimepiride	Type 2 diabetes
8	Jentadueto	Linagliptin + Metformin	Type 2 diabetes
9	Avandamet	Metformin + Rosiglitazone	Type 2 diabetes
10	Avandaryl	Glimepiride + Rosiglitazone	Type 2 diabetes
11	Prandimet	Metformin + Repaglinide	Type 2 diabetes
12	Metaglip	Metformin + Glapizide	Type 2 diabetes
13	Glyxambi	Empagliflozin+ Linagliptin	Type 2 diabetes
14	Synjardy	Empagliflozin + Metformin	Type 2 diabetes
15	Oseni	Alogliptin+ Pioglitazone	Type 2 diabetes
16	Kazono	Alogliptin + Metformin	Type 2 diabetes
17	Janumet	Sitagliptin + Metformin	Type 2 diabetes
18	Actoplus Met	Pioglitazone + Metformin	Type 2 diabetes
19	Metaglip	Glipizide + Metformin	Type 2 diabetes

Adverse drug reaction

The World Health Organization (WHO) defined adverse drug reaction (ADR) as “a noxious, unintended, and undesirable effect which occurs as a result of dose normally in man for diagnosis, prophylaxis, and treatment of disease or modification of physiological function.” Some of the factors responsible for ADRs include drug interaction, polypharmacy, and disease complexity. In antidiabetic medication, pharmacovigilance is very important in analyzing, detecting ADRs and reporting to physicians on the details of events, thereby protecting the patients from avoidable adverse event⁴⁷. ADRs due to antidiabetic medication is a frequent problem. Although most of these events are not likely to be life-threatening, they can lead to cause various discomforts in several patients. Some of these ADRs are summarized below. Hypoglycemia is the foremost problem of treatment using insulin and other hypoglycemic agents. It the main barrier to safe fulfillment of optimal glycemia in type 1 and type 2 diabetes mellitus⁴⁸. Hyperglycemic agents are associated with various events leading to metabolic and nutritional disorders, gastrointestinal system disorders and central nervous system disorders. Glimepiride as a single dose or its combination with metformin incidentally can cause hypoglycemia in patients. The metformin-induce dyspepsia which arises when metformin is taken in a higher dose, i.e., 1000 mg/day. Additionally, Metformin with voglibose combination can lead to incidents of dyspepsia⁴⁹. In some patients, insulin injection could lead to immediate adverse reactions which are usually induced by an immunoglobulin-mediation mechanism. It usually occurs within the first hour of insulin administration. Clinical signs and symptoms in some patients might include urticarial, bronchospasm, angioedema, erythema and swelling at the site of injection, rhinitis, and anaphylaxis. However, there is a reduction in allergy since the introduction of human insulin preparations.

CONCLUSION:

Active collaboration between a dietitian who gives dietary advises to patients, diabetologists who is an expert in diagnosis and management of diabetes and a pharmacist or pharmacologists who help minimize the ADRs of the medication in a long-term will help in the effective management of DM. In general, alongside medication use, dietary adjustment, as well as improvement in physical activities, should be adhered to by patients to have an optimum glycaemia. The study suggests the use of combined therapeutic interventions which can be benefited drug synergistic effect, improve patient compliance as well as reduce the cost of medication for patients. The study suggests that ADRs can be minimized through monitoring patients after insulin injection adheres; which helps to observe an allergic reaction that may arise in some patients after insulin is injection. An allergological test which includes skin prick test and the intradermal test should perform to patients on their first use of medication which can help the patient to choose medication without an adverse effect. A reduce in ADRs in antidiabetic medication in patients. Healthcare providers can educate patients regarding drug interactions and drug use to benefit patients.

CONFLICT OF INTEREST:

Authors declared no conflict of interest.

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Received on 25.02.2019 Modified on 18.03.2019

Research J. Pharm. and Tech. 2019; 12(5):2597-2602.

DOI: 10.5958/0974-360X.2019.00436.0