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Diabetes Management DPP-4 Inhibitors
Drug Profile—Saxagliptin, a Novel Dipeptidyl Peptidase-4 Inhibitor for the
Treatment of Type 2 Diabetes
Baptist Gallwitz, MD, PhD
Professor of Medicine, Department of Medicine IV, Eberhard Karls University of Tübingen
Abstract
Saxagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor for the treatment of type 2 diabetes. It is a novel DPP-4 inhibitor with a high selectivity for
DPP-4 compared with other dipeptidyl peptidases and a duration profile designed for once-daily application. DPP-4 inhibitors enhance endogenous
concentrations of the incretin hormones glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide. This action leads to a glucose-dependent
stimulation of insulin and inhibition of glucagon secretion post-prandially. DPP-4 inhibitors have no intrinsic risk of hypoglycemia and are weight-
neutral. Saxagliptin has been approved in the US and other countries. Phase I clinical trials demonstrated a dose-dependent inhibition of DPP-4 by
saxagliptin in a dose range from 2.5 to 100mg daily without serious side effects. Patients with type 2 diabetes receiving 10mg saxagliptin once-daily
in phase II trials showed a lowering of HbA
1c
and glucose together with good tolerability and safety. Phase III clinical studies demonstrated a good
efficacy regarding glycemic parameters in different patient populations, either in monotherapy or in combination with metformin, as well as a
favorable cardiovascular profile.
Keywords
Type 2 diabetes, diabetes therapy, dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors), saxagliptin, incretin-based therapy, glucagon-like
peptide 1 (GLP-1)
Disclosure: Baptist Gallwitz, MD, PhD, is a member of the advisory boards of AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Lilly, Novartis, Novo Nordisk, Merck, Roche,
and Takeda, and has also received honoraria for giving lectures from these companies.
Received: October 28, 2009 Accepted: December 4, 2009
Correspondence: Baptist Gallwitz, MD, PhD, Department of Medicine IV, Eberhard Karls University, Otfried-Müller-Str. 10, 72076 Tübingen, Germany.
E: baptist.gallwitz@med.uni-tuebingen.de
The worldwide prevalence of type 2 diabetes is rising dramatically, metformin and glitazones act on insulin resistance, and alpha-
leading to an increase in the complications of this disease. The total glucosidase inhibitors delay the breakdown of complex carbohydrates.
number of people with diabetes may reach 440 million worldwide by Exogenous insulin replaces the endogenous secretory insulin deficit,
2030.
1
Due to this development, and the fact that most patients do not although it potentially causes weight gain and hypoglycemia. The
reach their therapeutic goals, novel, effective, and safe treatment progressive loss of islet function observed in type 2 diabetes is not
options are needed. ameliorated by any of the current therapeutic options.
3
Type 2 diabetes is characterized by insulin resistance and islet cell The incretin hormones glucose-dependent insulinotropic peptide (GIP)
dysfunction. While insulin resistance is constant in the course of type 2 and glucagon-like peptide-1 (GLP-1) stimulate insulin secretion after a
diabetes, islet function continuously declines and is the driving force for meal. They are responsible for the fact that orally administered glucose
disease progression. Hyperglycemia, free fatty acids, cytokines, evokes a greater insulin response than an intravenously administered
adipokines, and toxic metabolic products aggravate the loss of beta-cell glucose infusion calculated to lead to identical serum glucose
function and mass. In addition, the alpha cells in the islets develop a excursions. This phenomenon is termed the incretin effect and is caused
glucagon secretion disturbance. In healthy subjects, glucagon secretion by the above-mentioned incretin hormones.
4
The incretin effect is
is suppressed under hyperglycemic conditions, whereas in type 2 reduced or even absent in patients with type 2 diabetes.
5
diabetes secretion is elevated, possibly contributing to excessive
glucose production by the liver.
2
The promising therapeutic potential of GLP-1 as a pharmacological tool for
treating type 2 diabetes was discovered in the 1990s. In contrast to other
The therapeutic options currently available are limited and do not insulinotropic agents, e.g. sulfonylureas, the insulinotropic effect of GLP-1
address the problem of islet-cell dysfunction. Classic insulin secretagogs depends on the actual glucose concentration, providing the possibility of
(sulfonylureas and glinides) exclusively stimulate insulin secretion, glucose normalization without the risk of hypoglycemia. In patients with
70 © TOUCH BRIEFINGS 2009
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