Initial Combination Therapy With Sitagliptin, a Dipeptidyl Peptidase-4 Inhibitor, and Metformin for Patients With Type 2 Diabetes Mellitus

Tina Vilsbøll


Expert Rev Endocrinol Metab. 2008;3(1):13-19. 

In This Article

Abstract and Introduction

The two incretin hormones, glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide potentiate nutrient-dependent insulin secretion following meal ingestion. Metabolic control can be improved markedly by administration of exogenous GLP-1, but the native peptide is almost immediately degraded by the enzyme dipeptidyl peptidase (DPP)-4 and, therefore, has little clinical value. Oral formulations that inhibit DPP-4, thereby prolonging the duration of endogenous incretin action, have, therefore, been developed. Sitagliptin, a once-daily, orally active, competitive and fully reversible inhibitor of DPP-4, was, as first in its class, introduced to the market as Januvia™. Recently, the US FDA approved initial combination therapy with sitagliptin and metformin (Janumet™) in order to help more patients with Type 2 diabetes mellitus get closer to accepted glycemic control targets, as recommended by standard guidelines. This article reviews initial treatment with Janumet as an alternative to monotherapy.

Type 2 diabetes mellitus (T2DM) has become a huge socioeconomic global burden over the last few decades and its prevalence is still increasing.[1] Patients with T2DM are characterized by multiple defects contributing to hyperglycemia, including inappropriate insulin secretion and insulin resistance.[2,3] Furthermore, patients with T2DM are also characterized by elevated fasting plasma glucagon concentrations that fail to decrease or, paradoxically, may even increase after carbohydrate ingestion, leading to excessive hepatic glucose production.[4,5,6] Thus, T2DM represents a complex disease and optimal treatment requires a multifaceted approach. Initial oral antidiabetic drugs (OADs) in monotherapy are often insufficient at getting patients to glycemic goals and, as the glycemic targets recommended by guidelines are lowered, even fewer patients will achieve the goals with single-agent therapy.[7,8,9,10] Additionally, many patients remain inadequately treated, because existing therapies have a number of shortcomings, including inadequate efficacy in glucose lowering, limited durability of glycemic response, inconvenient dosing regimens and safety and tolerability issues. The latter includes hypoglycemia (sulfonylureas, meglitinides and insulin), body weight gain (sulfonylureas, meglitinides, insulin and thiazolidinediones [TZDs]) and gastrointestinal intolerance (metformin and α-glucosidase inhibitors).[9] Although glucose control with metformin appears to decrease the risk of diabetes-related end points,[10] as the disease progresses, the drug is often not sufficient to obtain acceptable glycemic control after some years.[10] Therefore, new medical therapies that offer improved efficacy and/or durability, better convenience and an improved safety and tolerability profile are absolutely imperative in order to get more patients to goal initially and to avoid or delay the need for subsequent treatment.

For many years, diabetologists have been interested in the connection between the intestine, insulin secretion and glucose control. Recent studies have shown that the gut hormones, glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP) are of major importance in the glucose homeostasis of healthy subjects. These hormones are peptides, secreted from small intestinal endocrine cells rapidly after eating, with carbohydrates, fat and protein each acting as stimulants to secretion,[11] with further regulation by a complex neurohumoral system.[12] GLP-1 and GIP share common actions on islet ß-cells, acting through structurally distinct, yet related, receptors to cause glucose-dependent insulin secretion. In preclinical models, the peptides promote expansion of ß-cell mass by induction of ß-cell proliferation and reduction in apoptosis.[13,14] Furthermore, GLP-1 promotes glucose-dependent inhibition of glucagon secretion, slowing of gastric emptying and, through its central role in appetite regulation, promotes satiety, with sustained GLP-1 receptor activation being associated with weight loss in clinical studies.[15] In patients with T2DM, the secretion of GLP-1, but not GIP, appears to be diminished following meal ingestion. Nevertheless, in these patients, the physiological actions of GLP-1 are preserved, whereas acute administration of GIP is associated with diminished augmentation of insulin secretion relative to nondiabetic healthy controls.[13] These properties have made GLP-1 a prime target for diabetes therapies. Continuous intravenous or subcutaneous infusion of GLP-1 significantly improves glycemic control in patients with T2DM,[16,17] but the enzyme dipeptidyl peptidase (DPP)-4 rapidly inactivates the native hormone and, hence, renders the native peptide as an inconvenient treatment.[18,19,20,21] Therefore, two major approaches have been developed:[18]

  • Long-acting DPP-4-resistant analogues of GLP-1 (incretin mimetics)

  • DPP-4 inhibitors (incretin enhancers), proposed as a means of exploiting incretin hormone-based therapy

Incretin mimetics demonstrate sustained effect on glycemic control and significant reductions in bodyweight. In 2005, the first incretin mimetic (exenatide, a twice-daily injectable therapy) was introduced to the US market, and many others are in clinical development.[22] Patients treated with GLP-1 analogues experience weight loss, which can be substantial in approximately 20% and stands in contrast to the weight gain commonly seen with standard OADs.[22] Nausea is a common side effect, although often reported as mild to moderate and transient. A large number of DPP-4 inhibitors are also in clinical development. Sitagliptin (Januvia™, MK-0431) was recently licensed both in the USA and Europe for the treatment of T2DM, while vildagliptin (Galvus®) is expected on the market in 2008, and several other compounds are in late clinical development and are likely to join the market in the near future. This article reviews the mechanisms of action, efficacy, safety and tolerability of sitagliptin as well as initial combination treatment (sitagliptin and metformin) as an alternative to monotherapy.


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