Dipeptidyl peptidase 4 inhibitors (DPP4i) have been available for treating type 2 diabetes mellitus since 2006. Although they are a diverse group, DPP4i are all small, orally available molecules that ...interact with the catalytic site of DPP4 without disturbing any of its other known functions, including its effects on the immune system. DPP4i have no intrinsic glucose-lowering activity, so their efficacy as anti-diabetic agents is related directly to their ability to inhibit DPP4 activity and is mediated through the effects of the substrates they protect. Of these, the incretin hormone, glucagon-like peptide 1, is probably the most important. As the effects of glucagon-like peptide 1 are glucose-dependent, the risk of hypoglycaemia with DPP4i is low. Class effects, which are directly related to the mechanism of action, are common to all DPP4i; these include their overall good safety profile and tolerability, as well as their efficacy in improving glycaemic control, but also, potentially, a small increased risk of acute pancreatitis. Compound-specific effects are those related to their differing chemistries and/or pharmacokinetic profiles. These compound-specific effects could affect the way in which individual DPP4i are used therapeutically and potentially explain off-target adverse effects, such as hospitalization for heart failure, which is seen only with one DPP4i. Overall, DPP4i have a favourable therapeutic profile and are safe and effective in the majority of patients with type 2 diabetes mellitus.
Dipeptidyl peptidase-4 (DPP-4), also known as the T-cell antigen CD26, is a multi-functional protein which, besides its catalytic activity, also functions as a binding protein and a ligand for a ...variety of extracellular molecules. It is an integral membrane protein expressed on cells throughout the body, but is also shed from the membrane and circulates as a soluble protein in the plasma. A large number of bioactive molecules can be cleaved by DPP-4
, but only a few of these have been demonstrated to be physiological substrates. One of these is the incretin hormone, glucagon-like peptide-1 (GLP-1), which plays an important role in the maintenance of normal glucose homeostasis, and DPP-4 has been shown to be the key enzyme regulating its biological activity. This pathway has been targeted pharmacologically through the development of DPP-4 inhibitors, and these are now a successful class of anti-hyperglycaemic agents used to treat type 2 diabetes (T2DM). DPP-4 may additionally influence metabolic control via its proteolytic effect on other regulatory peptides, but it has also been reported to affect insulin sensitivity, potentially mediated through its non-enzymatic interactions with other membrane proteins. Given that altered expression and activity of DPP-4 are associated with increasing body mass index and hyperglycaemia, DPP-4 has been proposed to play a role in linking obesity and the pathogenesis of T2DM by functioning as a local mediator of inflammation and insulin resistance in adipose and hepatic tissue. As well as these broader systemic effects, it has also been suggested that DPP-4 may be able to modulate β-cell function as part of a paracrine system involving GLP-1 produced locally within the pancreatic islets. However, while it is evident that DPP-4 has the potential to influence glycaemic control, its overall significance for the normal physiological regulation of glucose homeostasis in humans and its role in the pathogenesis of metabolic disease remain to be established.
The first clinical study to investigate effects of dipeptidyl peptidase‐4 (DPP‐4) inhibition was published in 2002, and since then, numerous randomized controlled trials (RCTs) have shown that DPP‐4 ...inhibitors are efficacious, safe and well‐tolerated. This review will focus upon RCTs which have investigated DPP‐4 inhibitors in patient groups which are often under‐represented or excluded from typical phase 3 clinical trials. Large cardiovascular (CV) safety outcome trials in patients with established CV disease have confirmed that DPP‐4 inhibitors are not associated with any additional CV risk in these already‐at‐high‐risk individuals, while raising awareness of any uncommon adverse events, such as heart failure hospitalization seen in one of the trials. Studies in patients with kidney disease have shown DPP‐4 inhibitors to be efficacious without increasing the risk of hypoglycaemia, irrespective of the degree of renal impairment, while data from the large CV trials as well as smaller RCTs have even pointed towards potential renoprotective effects such individuals. The use of DPP‐4 inhibitors with insulin when therapy requires intensification may be beneficial without affecting the incidence or severity of hypoglycaemia, with these effects also being replicated in patients with chronic kidney disease, for whom other agents may not be suitable. Attention is now turning towards exploring the potential utility of DPP‐4 inhibitors in other circumstances, including for in‐hospital management of hyperglycaemia and in other metabolic disorders. Together, these RCTs raise the possibility that in the future, DPP‐4 inhibitors may have a broader use which may extend beyond glycaemic control in the typical type 2 diabetes mellitus (T2DM) patient seen in general practice and may encompass conditions other than T2DM.
•Understanding peptide degradation is useful to identify new drug targets.•Rational drug design can be based on prior knowledge of an underlying mechanism.•DPP-4 inhibitors were developed based on ...knowledge of incretin hormone biology.•Clinical effects of DPP-4 inhibitors may involve additional physiological substrates.
Dipeptidyl peptidase-4 (DPP-4) inhibitors are now a widely used, safe and efficacious class of antidiabetic drugs, which were developed prospectively using a rational drug design approach based on a thorough understanding of the endocrinology and degradation of glucagon-like peptide-1 (GLP-1). GLP-1 is an intestinal hormone with potent insulinotropic and glucagonostatic effects and can normalise blood glucose levels in patients with type 2 diabetes, but the native peptide is not therapeutically useful because of its inherent metabolic instability. Using the GLP-1/DPP-4 system and type 2 diabetes as an example, this review summarises how knowledge of a peptide’s biological effects coupled with an understanding of the pathways involved in its metabolic clearance can be exploited in a rational, step-by-step manner to develop a therapeutic agent, which is effective and well tolerated, and any side effects are minor and largely predictable. Other peptides with metabolic effects which can also be degraded by DPP-4 will be reviewed, and their potential role as additional mediators of the effects of DPP-4 inhibitors will be assessed.
•Endogenous immunoreactive GIP comprises multiple isoforms.•Measurement of GIP is complicated.•Insulinotropic and glucagontropic actions of GIP may contribute to the therapeutic profile of DPP-4 ...inhibitors.
Glucose-dependent insulinotropic polypeptide (GIP) is a gastrointestinal hormone with insulinotropic and glucagonotropic actions, and is believed to be the more physiologically important incretin hormone in healthy humans. Together with the other incretin hormone, glucagon-like peptide-1 (GLP-1), it plays an important role in regulating glucose homeostasis. Both GLP-1 and GIP are substrates of the enzyme dipeptidyl peptidase-4 (DPP-4), and DPP-4 inhibitors, which potentiate their effects on glycaemic control, are now used to treat type 2 diabetes (T2D). This review describes how post-translational processing of the GIP precursor molecule and post-release degradation of the secretory products give rise to multiple isoforms of GIP, some, but not all of which are biologically active, and discusses how this impacts upon their measurement by immunological- and bioassay-based methods. DPP-4 inhibitors reduce degradation of GIP, and although the insulinotropic effects of GIP are impaired in patients with T2D, they can be at least partially restored if glycaemic control is improved. Therefore, given that studies with incretin receptor antagonists indicate that not all of the glucose-lowering effects of DPP-4 inhibition can be accounted for by GLP-1 alone, evidence supports the notion that GIP may play a role in mediating the anti-hyperglycaemic effects of DPP-4 inhibition, while its glucagonotropic actions at lower glucose levels may contribute to the low risk of hypoglycaemia associated with DPP-4 inhibitors.
Therapeutic Strategies Based on Glucagon-Like Peptide 1
Carolyn F. Deacon
Department of Medical Physiology, The Panum Institute, Copenhagen, Denmark
Address correspondence and reprint requests to Dr. ...C.F. Deacon, Department of Medical Physiology, Panum Institute, Blegdamsvej
3, DK-2200 Copenhagen N, Denmark. E-mail: deacon{at}mfi.ku.dk
Abstract
Glucagon-like peptide (GLP)-1 is an incretin hormone with potent glucose-dependent insulinotropic and glucagonostatic actions,
trophic effects on the pancreatic β-cells, and inhibitory effects on gastrointestinal secretion and motility, which combine
to lower plasma glucose and reduce glycemic excursions. Furthermore, via its ability to enhance satiety, GLP-1 reduces food
intake, thereby limiting weight gain, and may even cause weight loss. Taken together, these actions give GLP-1 a unique profile,
considered highly desirable for an antidiabetic agent, particularly since the glucose dependency of its antihyperglycemic
effects should minimize any risk of severe hypoglycemia. However, its pharmacokinetic/pharmacodynamic profile is such that
native GLP-1 is not therapeutically useful. Thus, while GLP-1 is most effective when administered continuously, single subcutaneous
injections have short-lasting effects. GLP-1 is highly susceptible to enzymatic degradation in vivo, and cleavage by dipeptidyl
peptidase IV (DPP-IV) is probably the most relevant, since this occurs rapidly and generates a noninsulinotropic metabolite.
Strategies for harnessing GLP-1’s therapeutic potential, based on an understanding of factors influencing its metabolic stability
and pharmacokinetic/pharmacodynamic profile, have therefore been the focus of intense research in both academia and the pharmaceutical
industry. Such strategies include DPP-IV–resistant GLP-1 analogs and selective enzyme inhibitors to prevent in vivo degradation
of the peptide.
DPP-IV, dipeptidyl peptidase IV
GIP, glucose-dependent insulinotropic polypeptide
GLP, glucagon-like peptide
NEP, neutral endopeptidase
OAA, oral antidiabetic agent
Footnotes
C.F.D. is a paid consultant for Novo Nordisk.
Accepted May 27, 2004.
Received April 1, 2004.
DIABETES
The incretin hormones are released during meals from gut endocrine cells. They potentiate glucose-induced insulin secretion and may be responsible for up to 70% of postprandial insulin secretion. The ...incretin hormones include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), both of which may also promote proliferation/neogenesis of beta cells and prevent their decay (apoptosis). Both hormones contribute to insulin secretion from the beginning of a meal and their effects are progressively amplified as plasma glucose concentrations rise. The current interest in the incretin hormones is due to the fact that the incretin effect is severely reduced or absent in patients with type 2 diabetes mellitus (T2DM). In addition, there is hyperglucagonaemia, which is not suppressible by glucose. In such patients, the secretion of GIP is near normal, but its effect on insulin secretion, particularly the late phase, is severely impaired. The loss of GIP action is probably a consequence of diabetes, since it is also observed in patients with diabetes secondary to chronic pancreatitis, in whom the incretin effect is also lost. GLP-1 secretion, on the other hand, is also impaired, but its insulinotropic and glucagon-suppressive actions are preserved, although the potency of GLP-1 in this respect is decreased compared to healthy subjects. However, in supraphysiological doses, GLP-1 administration may completely normalize beta as well as alpha cell sensitivity to glucose. The impaired action of GLP-1 and GIP in T2DM may be at least partly restored by improved glycaemic control, as shown in studies involving 4 weeks of intensive insulin therapy. The reduced incretin effect is believed to contribute to impaired regulation of insulin and glucagon secretion in T2DM, and, in support of this, exogenous GLP-1 administration may restore blood glucose regulation to near normal levels. Thus, the pathogenesis of T2DM seems to involve a dysfunction of both incretins. Enhancement of incretin action may therefore represent a therapeutic solution. Clinical strategies therefore include the development of metabolically stable activators of the GLP-1 receptor; and inhibition of DPP-4, the enzyme that destroys native GLP-1 almost immediately. Orally active DPP-4 inhibitors and the metabolically stable activators, exenatide (Byetta), are now on the market, and numerous clinical studies have shown that both principles are associated with durable antidiabetic activity.
Introduction:
Dipeptidyl peptidase (DPP)-4 inhibitors belong to one class of drugs that have been approved for treatment of type 2 diabetes (T2D) based on the glucose-lowering actions of the ...gastrointestinal hormone glucagon-like peptide (GLP)-1. Several different compounds are now available, and although their mechanism of action (inhibition of the catalytic activity of DPP-4) is the same, there are fundamental differences between them.
Areas covered:
The authors discuss the differences between different DPP-4 inhibitors and review their therapeutic efficacy and key safety data. The literature covered includes original studies and meta-analyses identified in PubMed, recent abstracts presented at major diabetes scientific conferences, and clinical trials registered at ClinicalTrials.gov.
Expert opinion:
Although there are some differences in the pharmacokinetic and pharmacodynamic profiles of the different DPP-4 inhibitors, all are small orally active compounds with broadly similar HbA1c-lowering efficacy. They improve glycaemic control in T2D, without increasing the risk of hypoglycaemia or causing weight gain. They can be used as monotherapy or in combination with other anti-diabetic therapies, including insulin, regardless of renal or hepatic function, and are efficacious across the spectrum of patients with T2D, including those with long-standing disease duration. DPP-4 inhibitors may also have beneficial effects beyond glycaemic control, although this remains to be demonstrated in purpose-designed clinical trials.
Nutrient "preloads" given before meals can attenuate postprandial glycemic excursions, at least partly by slowing gastric emptying and stimulating secretion of the incretins (i.e., glucagon-like ...peptide-1 GLP-1 and glucose-dependent insulinotropic polypeptide GIP). This study was designed to evaluate whether a protein preload could improve the efficacy of the dipeptidyl peptidase-4 (DPP-4) inhibitor vildagliptin to increase incretin concentrations, slow gastric emptying, and lower postprandial glycemia in type 2 diabetes.
Twenty-two patients with type 2 diabetes treated with metformin were studied on four occasions, receiving either 50 mg vildagliptin (VILD) or placebo (PLBO) on both the evening before and the morning of each study day. The latter dose was followed after 60 min by a preload drink containing either 25 g whey protein (WHEY) or control flavoring (CTRL), and after another 30 min by a (13)C-octanoate-labeled mashed potato meal. Plasma glucose and hormones, and gastric emptying, were evaluated.
Compared with PLBO/CTRL, PLBO/WHEY reduced postprandial peak glycemia, increased plasma insulin, glucagon, and incretin hormones (total and intact), and slowed gastric emptying, whereas VILD/CTRL reduced both the peak and area under the curve for glucose, increased plasma intact incretins, and slowed gastric emptying but suppressed plasma glucagon and total incretins (P < 0.05 each). Compared with both PLBO/WHEY and VILD/CTRL, VILD/WHEY was associated with higher plasma intact GLP-1 and GIP, slower gastric emptying, and lower postprandial glycemia (P < 0.05 each).
In metformin-treated type 2 diabetes, a protein preload has the capacity to enhance the efficacy of vildagliptin to slow gastric emptying, increase plasma intact incretins, and reduce postprandial glycemia.
The prevalence of type 2 diabetes is increasing, which is alarming because of its serious complications. Anti‐diabetic treatment aims to control glucose homeostasis as tightly as possible in order to ...reduce these complications. Dipeptidyl peptidase‐4 (DPP‐4) inhibitors are a recent addition to the anti‐diabetic treatment modalities, and have become widely accepted because of their good efficacy, their benign side‐effect profile and their low hypoglycaemia risk. The actions of DPP‐4 inhibitors are not direct, but rather are mediated indirectly through preservation of the substrates they protect from degradation. The two incretin hormones, glucagon‐like peptide‐1 and glucose‐dependent insulinotropic polypeptide, are known substrates, but other incretin‐independent mechanisms may also be involved. It seems likely therefore that the mechanisms of action of DPP‐4 inhibitors are more complex than originally thought, and may involve several substrates and encompass local paracrine, systemic endocrine and neural pathways, which are discussed here.
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