Linagliptin: A Review on Therapeutic Role in Diabetes Mellitus.


Smita S. Aher1, Saroj P. Gajare2, Ravindra B. Saudagar1

1Department of Pharmaceutical Chemistry, R. G. Sapkal College of Pharmacy, Anjaneri, Nasik.

2Department of Quality Assurance Techniques, R. G. Sapkal College of Pharmacy, Anjaneri, Nasik.

*Corresponding Author E-mail:



Diabetes mellitus is a chronic condition prevalent worldwide. It is estimated that more than 246 million individuals have diabetes, with this number expected to increase to 366 million by the year 2030. The chronic hyperglycemia of diabetes is associated with long term damage to various organs, including the eyes, kidneys, nervous system, heart, and vasculature. India has a long history regarding the epidemiology of diabetes. In an effort to optimize glycemic control and also to reduce the burden of diabetic complications, several classes of oral hypoglycemic agents have been developed. Linagliptin has now been on the market and has been established as the first-line agent of choice for the management of type 2 diabetes. In this way, linagliptin is anticipated to reduce insulin resistance, contribute to weight loss, and play a significant role in the improvement of cardiovascular outcomes.


KEYWORDS: Linagliptin, Diabetes, Hyperglycemia.





During the last 20 years type 2 diabetes mellitus has become a major health issue reaching epidemic proportions.1 It has recently been estimated that nearly 6% of the world’s adult populations are affected by this condition.2 As a result, patients have a considerably increased risk of vascular disease, which may affect macrovascular, i.e. cerebrovascular, coronary and peripheral arterial disease and microvascular disease, i.e. retinopathy, neuropathy and nephropathy.3,4Overall, these chronic vascular complications lead to increased morbidity and mortality.5 Diabetes mellitus is a chronic condition prevalent


Worldwide. It is estimated that more than 246 million individuals have diabetes, with this number expected to increase to 366 million by the year 2030.6 The chronic hyperglycemia of diabetes is associated with long term damage to various organs, including the eyes, kidneys, nervous system, heart, and vasculature. In addition, it is among the leading causes of blindness and renal failure worldwide.(7, 8) It is the fourth leading cause of death by disease and every 10 seconds a person dies from diabetes-related causes in the world. Each year, over three million deaths worldwide are tied directly to diabetes.


Type 2 diabetes is characterized by both disorders of insulin activity as well as inadequate insulin production by the pancreatic beta cells,9 and is the most common form of diabetes, comprising 90% to 95% of all diabetes cases.10 It is a disorder that affects the way the body uses digested food for growth and energy. Normally, the food one eats is broken down into glucose, a form of sugar. The glucose then passes into the bloodstream, where it is used by the cells for growth and energy. For glucose to reach the cells, however, insulin must be present. Insulin is a hormone produced by the pancreas, a fist-sized gland behind the stomach. Most people with type 2 diabetes have two problems: insulin resistance — a condition in which muscle, liver, and fat cells do not use insulin properly and reduced insulin production by the pancreas. As a result, glucose builds up in the blood, overflows into the urine, and passes out of the body, never fulfilling its role as the body’s main source of fuel.


India the diabetes capital of the world:

India has a long history regarding the epidemiology of diabetes. Charaka Samhita, the ancient Indian medical treatise, describes this condition and suggests that being obese was a major risk factor.11 Diabetes has emerged as a major healthcare problem in India having the highest number of diabetic patients in the world posing an enormous health problem in the country. According to the International Diabetes Federation, there were an estimated 40 million persons with diabetes in India in 2007 and this number is predicted to rise to almost 70 million people by 2025. It is estimated that every fifth person with diabetes will be an Indian. Due to these sheer numbers, the economic burden due to diabetes in India is amongst the highest in the world. The real burden of the disease is however due to its associated complications which lead to increased morbidity and mortality.


The International Diabetes Federation estimates that the number of diabetic patients in India more than doubled from 19 million in 1995 to 40.9 million in 2007. It is projected to increase to 69.9 million by 2025. The World Health Organization estimates that mortality from diabetes and heart disease cost India about $210 billion every year and is expected to increase to $335 billion in the next ten years. These estimates are based on lost productivity, resulting primarily from premature death thus calling India the diabetes capital of the world. Diabetes is the main cause of kidney failure, limbamputation, and new-onset blindness in Indian adults. People with diabetes are more likely than people without diabetes to develop and die from diseases of the heart and blood vessels, called cardiovascular disease. Adults with diabetes have heart disease death rates about two to four times higher than adults without diabetes, and the risk for stroke is two to four times higher among people with diabetes.


Risk Factors for Diabetes in Indians:

Type 2 diabetes mellitus epidemic in India is mainly because of sedentary lifestyle, lack of physical activity, obesity, stress and consumption of diets rich in fat, sugar and calories. Societal influences.12 various studies have shown that the high incidence of diabetes in India.



Insulin is a natural hormone produced in the pancreas, which enables cells to absorb glucose obtained from food and convert it into energy. In diabetes, the body either does not make enough insulin or does not respond properly to its own insulin, or both. Type II diabetes is characterized by cellular insulin resistance. The result is excess accumulation of glucose in the bloodstream as cells become resistant to the effects of insulin. As the type II diabetic condition progresses, many people gain weight and develop more fat cells13.


Treating type II diabetes with insulin-enhancing therapy increases the risk of cardiovascular complications, induces weight gain, and fails to correct the underlying cause of the disease Diet, exercise, proper medication and monitoring are essential in the management of diabetes. Uncontrolled diabetes can lead to various complications and organ damage involving almost all parts of the body.


Table 1: The Risk Factors for Diabetes in Indians





Indians develop diabetes at a very young age, at least 10 to 15 years earlier than the western population. An early occurrence of diabetes gives ample time for development of the chronic complications of diabetes.


The prevalence of diabetes increases with a family history of diabetes. The risk of a child developing diabetes with a parental history increases above 50 per cent

Central Obesity

The association of obesity with Type II Diabetes is well known. Even with an acceptable body weight range, weight gain could increase the risk of diabetes

Life style change

The availability of motorised transport combined with the plethora of television and internet programs has reduced the physical activity in all groups of populations is responsible for the development of diabetes

Insulin Resistance

Indians have been found to be more insulin resistant as compared to the other population. They have a higher level of insulin to achieve the same the blood glucose control. A cluster of factors consisting of abnormal fats, high blood pressure, obesity, and abnormal glucose levels known as metabolic syndrome is highly prevalent in Indians.


Urbanisation is associated with increasing obesity, decreasing physical activity due to changes in lifestyle, diet and a change from manual work to less physical occupations.

Physical and

mental Stress

The impact of stress both physical and mental along with lifestyle changes has a strong effect of increasing incidence of type II Diabetes



In an effort to optimize glycemic control and also to reduce the burden of diabetic complications, several classes of oral hypoglycemic agents have been developed.(14,15) An ideal anti-diabetic drug would enhance cellular insulin sensitivity, inhibit excess intestinal absorption of sugar, reduce excess liver production of glucose, promote weight loss and reduce cardiovascular risk factors. oral hypoglycemic agents used in the management of type 2 diabetes mellitus.16 Phenformin was the first biguanide to be marketed in the 1950’s, while buformin and metformin soon followed.17,18 This review outlines the use of metformin. Not only is this drug the most widely prescribed antidiabetic agent in the management of type 2 diabetes, but it has also been recommended as the first line treatment of choice in patients without contraindications.



Type 2 diabetes mellitus (T2DM) is a progressive disease, and it occurs with increasing prevalence in the elderly and those with other comorbidities. Blood glucose control presents a challenge that is magnified by these co-existing problems. To achieve glycemic targets, many patients need more than one antidiabetic drug, and additional medications are often required as glucose control deteriorates. Consequently, the development of new antidiabetic drugs that can help meet this challenge has been an area of intensive research. The dipeptidyl peptidase-4 (DPP-4) inhibitors are one of the recently developed therapeutic classes for treatment of hyperglycemia in T2DM. The various agents in the class have differing chemical structures, but all act by inhibiting the DPP-4 enzyme, thus prolonging the life of incretin hormones, which in turn raise insulin levels and suppress glucagon secretion in a glucose-dependent manner. As a class, DPP-4 inhibitors have been shown to provide significant improvements in glycosylated hemoglobin (HbA1c), and to have a good safety profile. In addition, their glucose dependent mechanism of action is associated with a low rate of hypoglycemic events High-throughput screening using an assay to detect inhibition of DPP-4 led to the discovery of linagliptin, a xanthine-based molecule with a high selectivity for DPP-4. The pharmacokinetics and pharmacodynamics of linagliptin have been reviewed in detail elsewhere. Of note, unlike other DPP-4 inhibitors, which are predominantly excreted via the kidneys, linagliptin is mainly excreted unchanged via the enterohepatic system. Based on pharmacokinetic studies, no dose adjustment is needed for patients with renal or hepatic impairment. Early studies showed linagliptin is suitable for once-daily dosing, with similar reductions in HbA1c to those seen with other DPP-4 inhibitors and without clinically significant pharmacokinetic interactions when co-administered with other medications. On the basis of the early studies, an extensive clinical trial program was undertaken to assess the efficacy and safety of linagliptin. Of these, four pivotal trials, trials designed to meet US Food and Drug Administration (FDA) criteria for assessing efficacy and safety of a drug before it is approved for use in patients in the US, have been reported over the past year or so. The positive results of these trials led to FDA approval of Linagliptin to improve glycemic control in patients with T2DM in May 2011.



After oral administration the drug is rapidly absorbed and geometric mean values for the maximum plasma concentration for the maximum plasma concentration are approximately 6-10 nmol/L after a single dose, and 11-12 nmol/L at steady state. The time taken to achieve maximum plasma concentration is approximately 1.5-2.0 hr. The absolute bioavailability of Linagliptin has been estimated to be approximately 30%. The large apparent volume of distribution indicates extensive distribution of Linagliptin in the tissues. In addition, Linagliptin has been shown to bind extensively to plasma proteins (70-80%) in a concentration-dependent manner. The overall disposition and elimination of Linagliptin is mainly eliminated unchanged through feces. Its main metabolite (CD 1790) accounts for approximately 18% of the molar Linagliptin plasma exposure (AUC 24) after a single oral 10-mg dose of Linagliptin, and is pharmacologically inactive. Linagliptin is excreted through non-renal route, with 84.7% of an orally administered 10-mg dose being eliminated through bile and the gut, and 5.4% excreted in urine.



Linagliptin is an inhibitor of DPP-4, an enzyme that degrades the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulin tropic polypeptide (GIP). Both GLP-1 and GIP increase insulin biosynthesis and secretion from pancreatic beta cells in the presence of normal and elevated blood glucose levels. GLP-1 also reduces glucagon secretion from pancreatic alpha cells, resulting in a reduction in hepatic glucose output. Thus linagliptin stimulates the release of insulin in a glucose-dependent manner and decreases the levels of glucagon in the circulation.



Linagliptin is a weak-to-moderate inhibitor of cytochrome P450 enzymes. Because of the small proportion of Linagliptin that is metabolized by these enzymes, changes in exposure to Linagliptin by inhibition of induction of P450 dependent pathways by concomitantly administered drugs are considered to be unlikely. Importabtly, Linagliptin has shown no clinically relevant PK interactions with commonly prescribed antidiabetes drugs, such as metformin, pioglitazone and glyburide. Linagliptin is P-glycoprotein substrate, and fully efficacy of Linagliptin might not be achieved when administered in combination with strong inducers of P-glycoprotein such as rifampicin.


Linagliptin has unique pharmacological properties within the DPP-4 inhibitor class. The long terminal half-life of Linagliptin is related to its non-linear PK profile that results from strong binding to its primary target, DPP-4. Despite having a long terminal half-life, Linagliptin also exhibits a short accumulation half-life, which can be attributed to the saturable, high affinity binding to DPP-4. When DPP-4 is saturated, unbound linaliptin is rapidly cleared from body through bile and the gut. The PK characteristics of Linagliptin have an impact on its clinical utility, such that an oral dose of 5mg once daily is suitable for a broad ramge of patients with type-2 diabetes mellitus. In the contrast with other DPP-4 inhibitors, the largely non renal route of excretion of Linagliptin allows treatment to be administered to patients with renal impairment, without the need for dose adjustment. Although Linagliptin is largely metabolized in the liver, dose adjustment is not required for patients with hepatic impairment. This feature might may related to its wide therapeutic window and the fact that exposure to the Linagliptin is not substantially altered by the presence of hepatic impairment. The mg dose is also suitable for patients of Asian in ethnicity; small changes in PK parameters observed when Linagliptin is given to Japanese and Chinese patients have not been shown to have clinically relevant effect. Despite the fact that many clinical trials of Linagliptin have been carried out in largely caucasin populations, these findings provide reassurance that PK/PD properties of linaglipti are not altered to a clinically relavant extend in patients of Asian ethinicity.



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Received on 04.07.2017          Modified on 28.08.2017

Accepted on 26.09.2017        © RJPT All right reserved

Research J. Pharm. and Tech. 2017; 10(9): 3233-3236.

DOI: 10.5958/0974-360X.2017.00573.X