review article

Vildagliptin – A New Prospect in Management of Type 2 Diabetes SATISH BABU

Abstract Type 2 diabetes mellitus (T2DM) is a heterogeneous disease with multiple underlying pathophysiological processes and primarily affects the middle-aged and the elderly. However, recently the disease has been detected in adolescents due to the rising prevalence of obesity. The quality-of-life in these patients is characterized by chronic hyperglycemia, daily ordeal of self-management and life-long need for multiple medications. Despite availability of many antidiabetic therapies, optimizing glycemic control continues to be a challenge due to the progressive nature of the disease, which the existing oral antidiabetics (OADs) often fail to address. Also, the associated adverse effects limit their optimal use. The incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) have been focus of research in the last decade. These hormones regulate the release of insulin and glucagon from the pancreas, through a process termed as the incretin effect. Vildagliptin is a potent, selective and orally active dipeptidyl peptidase-4 (DPP-4) inhibitor, which prevents inactivation of incretin hormones by inhibiting DPP-4. It has been shown to be an effective and safe option for better glycemic control in a wide range of T2DM patients and has demonstrated HbA1C lowering potential when given as monotherapy or in combination with other OADs, without weight gain and minimal hypoglycemia. Keywords: Type 2 diabetes mellitus, incretins, dipeptidyl peptidase-4, vildagliptin, tolerability

T

ype 2 diabetes mellitus (T2DM) is a heterogeneous disease with multiple underlying pathophysiological processes characterized by hyperglycemia due to a progressive insufficiency of pancreatic β-cells in maintaining adequate regulatory levels of insulin secretion against backdrop of insulin resistance. Till recently, T2DM was primarily considered to be a disease affecting middle and elderly age group, but with the rising prevalence of obesity-associated T2DM, the disease has lately made its presence felt in adolescents and children,1, 2 presenting major health and socioeconomic challenges globally. According to latest figures from International Diabetes Federation (IDF), the number of people with diabetes mellitus is projected to rise from 366 million in 2011 to 552 million by the year 2030. In 2011, IDF estimates that India alone has 61.3 million people living with diabetes, placing India second to China.3 T2DM is perceived to account for nearly 85-95% of all reported cases of diabetes globally.4

Consultant Endocrinologist and Diabetologist, Bangalore Address for correspondence Dr Satish Babu Consultant Endocrinologist and Diabetologist No. 313/D, 9th ‘A’ Main, 6th Block, Jayanagar, Bangalore - 560 041 E-mail: [email protected]

The disease is characterized by chronic hyperglycemia, daily ordeal of self-management and life-long need for multiple medications; despite this, a large proportion of T2DM patients develop microvascular and macrovascular complications in due course of time,5 eventually affecting their quality-of-life. With 90% T2DM patients being overweight/obese at diagnosis,6 therapeutic modalities beside lifestyle modification involve, reducing body weight preferably with loss of central adiposity, increasing insulin availability and decreasing insulin requirements.7 Clinicians today have accessibility to wide range of oral antidiabetic drugs (OADs) for management of T2DM, with each medication class diverse in its mode of action (Table 1). Despite the availability of antidiabetic therapies, achieving optimal glycemic control, keeping in mind efficacy, safety and tolerability profile and not to forget cost of medication, continues to be a challenge. However, each of this drug class is associated with one or more adverse effects.8 Drugs like sulfonylureas (SUs), meglitinides and insulin are associated with weight gain and hypoglycemia; thiazolidinediones (TZDs) causes weight gain and possibly peripheral edema. Metformin and a-glucosidase inhibitors are associated with gut-related side effects (seen in ~50% of treated patients). Moreover, with the possible exception of the TZDs, glycemic control gradually worsens over time

Indian Journal of Clinical Practice, Vol. 22, No. 8, January 2012

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review article Table 1. Mechanisms of Action of OADs for the Treatment of Hyperglycemia in T2DM Agent

Mechanism of action

Meglitinides

Stimulate insulin secretion (more rapid onset 0.6-2% and shorter duration of action than SUs)

Monotherapy

Metformin

Counters insulin resistance (especially decreases hepatic glucose output)

1-2%

Monotherapy

Stimulate insulin secretion

1-2%

Sulfonylureas

HbA1C reduction

Indication Combination with metformin Combination with SUs, other insulin secretagogue, TZDs, insulin Monotherapy Combination with metformin, TZDs, α-glucosidases inhibitor, insulin

Thiazolidinediones Increase insulin sensitivity (especially increase peripheral glucose utilization)

1-2%

α-Glucosidases inhibitors

0.5-1%

Reduce rate of carbohydrate digestion

with most treatments.9,10 Concerns about the safety and tolerability (notably weight gain) have often limited the optimal application of SUs and TZDs. Additionally, the impact of different drugs, even within a single class, on the risk of long-term vascular complications has recently come under scrutiny.11 Among the OADs, TZDs till recently were increasingly used to treat T2DM and drug in initial years showed promising effect. But a decade after the launch of first TZDs, concerns have been expressed over the cardiovascular (CV) risks associated with TZDs. In a retrospective cohort study of 4,73,483 newly diagnosed T2DM patients, rosiglitazone monotherapy was found to be associated with higher risk for any CV event, than those receiving metformin monotherapy. Overall, add-on rosiglitazone and pioglitazone were associated with comparable CV risk.12 In addition, therapy with TZDs can cause weight gain of an extent similar to that observed with older SUs.13 TZDs, alone or in combination with other agents, may cause fluid retention. Because of this, patients with heart failure should be observed for signs and symptoms of worsened cardiac status; patients with New York Heart Association class III or IV cardiac status should not be prescribed TZDs.14 A recently identified additional safety concern with TZDs therapy is an increased risk of fractures; data suggest that treatment with TZDs contributes to bone loss and the effect being most prominent in postmenopausal women.15 A study in Scotland assessed the relationship between TZDs exposure and fracture in 2,12,000 patients and found increased risk for hip fracture associated with TZDs use, in both men and women alike.16

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Indian Journal of Clinical Practice, Vol. 22, No. 8, January 2012

Monotherapy Combination with metformin, SUs ,insulin (pioglitazone only in combination with insulin) Monotherapy Combination with SUs

Though, existing OADs are usually effective in attaining short-to-medium term treatment goals in T2DM, but disease being progressive in nature, traditional treatment algorithms often fail to address this issue. Also, dysfunction of a-cells that is also present in T2DM has been overlooked all these years, primarily because of want of therapeutic options. The necessity to tackle issue of fundamental islet cell deficit led to a search for therapeutic alternatives, leading to rediscovery of the incretin hormones and their role in glucose homeostasis. Better understanding of their potential has in turn led to the development of incretin analogs and incretin enhancers for treatment of T2DM.17-19 Diabetes and the Incretin Hormones The incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-likepeptide-1 (GLP-1) that stimulate insulin secretion are secreted from the gastrointestinal tract during food intake. They regulate insulin and glucagons release from the pancreas, through a process termed as the incretin effect.20 GLP-1 has also been shown to suppress glucagon secretion, slow gastric emptying and reduce food intake and body weight.21-24 But T2DM patients have reduced incretin effect, combined with constant decline in pancreatic α- and β-cell function, leading to progressive loss of glycemic control. This manifests as diminishing of glucose-dependent insulin release and progression to unregulated glucagon production, respectively.20,25,26 Since, GLP-1 secretion is lower than normal in T2DM and increasing GLP-1 decreases glycemia, it was theorized that reducing GLP-1 degradation may compensate for its reduced

review article Table 2. Incretins Action in T2DM Patients Deficiencies in T2DM

Actions of incretins

Impaired glucose-stimulated insulin secretion and lack of postprandial biphasic response

Restoration of glucose-dependent insulinotropic effect and first-phase response

Hyperglucagonemia

Suppression of glucagon secretion

Defective hypoglycemia counter-regulation

Glucagon secretion, and loss of insulinotropic effect, when plasma glucose is low

Reduced β-cell mass and insulin content

Increased synthesis of proinsulin, possible increased β-cell mass or differentiation of islet precursor cells into β-cells

Accelerated β-cell apoptosis

Possible inhibition of toxin-induced β-cell apoptosis

Normal, retarded or accelerated gastric emptying

Slowing of gastric emptying

Hypercaloric energy intake, obesity

Suppression of appetite/increased satiety, weight loss Source: Khoo J, Raytner CK, Jones KL, et al. Ther Clin Risk Manag 2009;5:683-98.

secretion in T2DM, since, despite impaired GLP-1 secretion its effects are preserved and GIP secretion remains normal but with reduced insulinotropic effect.26 The actions of incretins on the deficiencies in glucose metabolism, pancreatic function and energy intake in T2DM patients are shown in Table 2. The major therapeutic drawback to using native incretins is their very short half-life (