Specialities

Specialities

Bone Disorders
Cardiovascular Risk
COVID-19
Diabetes
Endocrine Oncology
General Endocrinology
Obesity
Paediatric Endocrinology
Pituitary Disorders
Reproductive Endocrinology
Thyroid Disorders
Chronic Kidney Disease
Liver Disorders
Adrenal Disorders
Search

Trending Topic

Stastical analysis indication diabetes mellitus .generative ai
5 mins

Trending Topic
Developed by Touch
Mark CompleteCompleted
BookmarkBookmarked

Forty-four Years of the UK Prospective Diabetes Study: Legacy Effect and Beyond

Saptarshi Bhattacharya, Sanjay Kalra, Lakshmi Nagendra

Very few trials in the history of medical science have altered the treatment landscape as profoundly as the UK Prospective Diabetes Study (UKPDS). Even 44 years after its inception, the trial and post-study follow-up findings continue to fascinate and enlighten the medical community. The study was conceived at a time when there was uncertainty about […]

touchREVIEWS in Endocrinology. 2024;21(1):1–2:Online ahead of journal publication

Connect With Us:

Facebook
X (Twitter)
Instagram
Youtube
Linkedin
Diabetes
6 mins

DPP-4 Inhibition as a Newly Emerging Therapy for Type 2 Diabetes

Carolyn F Deacon, Jens J Holst
Share
Facebook
X (formerly Twitter)
LinkedIn
Via Email
Mark CompleteCompleted
BookmarkBookmarked
Copy LinkLink Copied
Published Online: Jun 6th 2011 US Endocrinology, 2006;(2): DOI: http://doi.org/10.17925/USE.2006.00.02.1l
Select a Section…
1

Abstract

Overview

Type 2 diabetes mellitus (T2DM) is a progressive disease, characterized by insulin resistance, impaired glucose-induced insulin secretion, inappropriately elevated glucagon concentrations, and hyperglycemia. Many patients cannot obtain satisfactory glycemic control with current therapies, and eventually develop microvascular and macrovascular diabetic complications. New and more effective agents, targeted not only at treatment, but also at prevention of the disease, its progression, and its associated complications, are, therefore, required. One new approach focuses on the effects of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which enhance mealinduced insulin secretion.1

2

Article

In addition, GLP-1 has a spectrum of effects thought to be desirable in an antidiabetic agent, including trophic effects on β-cells, inhibition of glucagon secretion, and suppression of food intake and appetite.2,3 The native peptides cannot be used therapeutically because they are rapidly degraded and inactivated by the enzyme, dipeptidyl peptidase-4 (DPP-4). Two strategies have been proposed to overcome this drawback:4 the use of


In addition, GLP-1 has a spectrum of effects thought to be desirable in an antidiabetic agent, including trophic effects on β-cells, inhibition of glucagon secretion, and suppression of food intake and appetite.2,3 The native peptides cannot be used therapeutically because they are rapidly degraded and inactivated by the enzyme, dipeptidyl peptidase-4 (DPP-4). Two strategies have been proposed to overcome this drawback:4 the use of

  • long-acting stable analogs of GLP-1, the so-called incretin mimetics; and
  • inhibitors of DPP-4 to potentiate levels of the endogenously released active forms of the incretin hormones, the so-called incretin enhancers.

Compounds from both classes have recently been approved for therapy of T2DM.

Incretins and T2DM
In T2DM, pancreatic islet hormone secretion is inappropriate for the prevailing glycemia, while the accompanying insulin resistance contributes to an impairment of insulin action that may feed back to a further progressive deterioration in islet function.5 The UK Prospective Diabetes Study (UKPDS) demonstrated that β-cell function is already reduced by ~50% at the time of diagnosis, and continues to decline regardless of treatment.6 Additionally, recent studies indicate that β-cell volume in subjects with T2DM and impaired glucose tolerance (IGT) is reduced compared with matched individuals without T2DM, suggesting that this defect occurs early and is important in the pathogenesis of the disease, rather than simply arising as a consequence of hyperglycemia.7

There is also evidence that β-cell dysfunction occurs early in disease development. Subjects with IGT have reduced β-cell responsiveness to glucose.8 First-phase insulin secretion is reduced in non-diabetic offspring or first-degree relatives of patients with T2DM,9,10 and this is a powerful predictor for the progression to overt diabetes.5GLP-1 Actions
GLP-1 stimulates insulin secretion, but its effect depends on normal or elevated glucose levels; the risk of hypoglycemia due to elevated GLP-1 concentrations is thereby practically eliminated. In addition, insulin stores are maintained because insulin gene expression and all steps in insulin biosynthesis are stimulated.11 Studies in isolated human islets and rodents have demonstrated that GLP-1 has trophic effects on the β-cell, enhancing proliferation and differentiation12-14 and reducing apoptosis.15 Although these actions have still to be demonstrated clinically, the possibility arises that GLP-1 may be able to halt, or even reverse, the progressive loss of functional β-cell mass that occurs in T2DM.

GLP-1 also counteracts the hyperglucagonemia that occurs in T2DM by strongly inhibiting α-cell secretion.16 Again, this effect is glucose-dependent, and it has been demonstrated that that elevated GLP-1 concentrations do not impair the glucagon counterregulatory response to hypoglycemia.17

GLP-1 inhibits gastrointestinal motility and secretion,18 thereby delaying the supply of nutrients for absorption in the small intestine, and helping to reduce mealinduced glucose excursions. In healthy subjects, this appears to be more important than the insulinotropic effect in lowering postprandial glucose excursions.19

In humans, peripherally administered GLP-1 has a satiating effect,20,21 and when given over a prolonged period (six weeks) by continuous subcutaneous infusion results in significant weight loss.22

The Incretin Effect
The insulin response to oral glucose greatly outweighs its response to an isoglycemic intravenous glucose infusion23 due to the release of GLP-1 and GIP, which enhance β-cell responses to glucose.This phenomenon, the incretin effect,24 can account for up to 70% of oral glucose-induced insulin secretion in healthy subjects. In patients with T2DM, the incretin effect is severely impaired or absent,25 and is characterized by:

  • impaired secretion of GLP-1 (whereas GIP secretion is relatively normal);26,27
  • markedly impaired β-cell sensitivity to GLP-1, although its efficacy is at least partially preserved;28 and
  • completely abolished effect of GIP on second phase insulin secretion.29

These defects do not precede the development of diabetes, and have been suggested to be a consequence, rather than a cause, of the condition.30,31 However, once glucose control deteriorates, incretin defects are likely to contribute to the impaired insulin secretion that characterizes T2DM.30

Although β-cell responsiveness to glucose is reduced in patients with T2DM,28 this defect is completely corrected by GLP-1, even though β-cell sensitivity to GLP-1 itself is reduced.28 Biology and Actions of DPP-4

Enzymatic Action
DPP-4 is a membrane-bound serine peptidase, found in numerous sites, including the kidney and intestinal brush-border membranes, hepatocytes, T-cells, and vascular endothelial cells, as well as in a soluble form in plasma.32 It has strict substrate requirements, but in vitro kinetic studies revealed that both incretins were good substrates.33 The truncated metabolites comprise the majority of endogenous GLP-1 and GIP immunoreactivity in humans, suggesting that DPP-4 may be important in incretin hormone metabolism.34,35 This was confirmed by the demonstration that DPP-4 inhibition prevented the in vivo N-terminal degradation of exogenous and endogenous GLP-1 and GIP.36-38 GLP-1 in particular is degraded extremely rapidly.39,40 In vitro kinetic studies have indicated that a number of peptides can be degraded by DPP-4 (see Lambeir 200332 for review), but the physiological relevance (if any) has yet to be established for most of them.41

DPP-4 is identical to the T-cell antigen, CD26, and contributes to T-cell activation and proliferation.42 However, it appears that its catalytic activity is probably not involved, and that its presence is not obligatory for normal immune function, since animal models lacking DPP-4 activity are viable and seem to suffer no ill effects.43,44 In vitro studies comparing highly selective DPP-4 inhibitors and inhibitors for other related enzymes like DPP-8 and DPP-9 have demonstrated that the catalytic activity of these other enzymes, but not DPP-4, is involved in T-cell activation and proliferation.45 Furthermore, in long-term studies the DPP-4 inhibitors in clinical development have, to date, proved to be remarkably safe and well tolerated and have not been associated with immune side effects.

DPP-4 and T2DM
Several studies have found that concentrations of intact biologically active GLP-1 are reduced in patients with T2DM,26,27 raising speculation that a more extensive or rapid degradation of the incretin hormones may contribute to the reduced incretin effect observed. However, elimination of intact GLP-1 and GIP is identical in healthy subjects and patients with T2DM.40,46 There is some evidence that plasma DPP-4 activity may be positively correlated with glycated hemoglobin (HbA1c),47,48 but this seems not to correlate with active incretin hormone concentrations.48 Nevertheless, since up to 70–80% of endogenous GLP- 1 and ~50% of endogenous GIP circulates in the degraded form in humans,34,35 inhibition of this process has the potential to raise active incretin hormone concentrations into the range shown to be therapeutically useful.49DPP-4 Inhibitors and T2DM
DPP-4 inhibitors are low molecular weight compounds that are orally available.3 Vildagliptin is suitable for both once and twice daily dosing. It has low protein binding and 85% of the dose is renally excreted as a pharmacologically inactive metabolite.50 Sitagliptin is longer acting than vildagliptin,51 and differs by being excreted in the urine primarily as the unchanged parent drug.52 Saxagliptin53 and denagliptin54 (both currently in phase III trials) are also long-acting inhibitors with an expected once daily dosing regimen. Inhibitor PSN9301, formerly developed under the name P93/01, is currently in phase II trials, and has a rapid onset and short duration of action with dosing expected to be meal-related.55

Sitagliptin was approved as both monotherapy or in combination with metformin or thiazolidinediones in October 2006. Vildagliptin was submitted for regulatory approval in the US in spring 2006 (decision expected in early 2007) and in Europe in August 2006.

Pre-clinical Experience
Initial acute studies in normal and glucose-intolerant animal models confirming the anti-hyperglycemic effectiveness of DPP-4 inhibition were rapidly followed by longer-term studies with a variety of inhibitors in different animal models, all showing improvements in glucose tolerance.3 Rather fewer studies have investigated whether DPP-4 inhibition affects β-cell mass, although the number of β-cells and small islets were increased by DPP-4 inhibition in diabetic (streptozotocin-treated) rats and insulin-resistant high fat fed mice.56,57 Vildagliptin increased β-cell mass via effects on replication and apoptosis in neonatal rats.58 In a mouse model of impaired insulin sensitivity and secretion, a sitagliptin analog increased insulin-positive β-cell number, and restored the β-cell:α-cell ratio and distribution pattern.59 These studies, therefore, suggest that DPP-4 inhibitors can have beneficial effects on the pancreatic islets, although whether this is also the case in humans remains unknown.

Clinical Proof of Concept
The first clinical study with a DPP-4 inhibitor used the short-acting predecessor to vildagliptin, NVPDPP728.60 Patients with relatively mild T2DM (mean HbA1c, 7.4%) received the inhibitor twice or three times daily as monotherapy for four weeks, resulting in reduced fasting and postprandial glucose levels and a fall in HbA1c levels to 6.9%. Similar results were obtained with once-daily vildagliptin monotherapy.61 Intact GLP-1 concentrations increased two-fold, glucagon secretion was suppressed, and insulin levels were maintained despite the lower glucose concentrations (see Figure 1).

Figure 1: Effects of Vildagliptin on Meal Induced Active GLP-1, Glucose, Insulin, and Glucagon Concentrations61

Efficacy as Monotherapy
Three months of monotherapy with once or twice daily vildagliptin reduced fasting and postprandial glucose levels, and lowered HbA1c from baseline (7.7–8%) by an average of 0.6%, with those patients with more poorly controlled T2DM showing the greatest improvements.62,63 These reductions are sustainable, as shown in another study with vildagliptin (50mg bid) administered for 52 weeks (see Figure 2).64 Twice-daily sitagliptin gives similar results, dose dependently reducing fasting plasma glucose by up to 1.0mmol/L and HbA1c levels by up to 0.8% from baseline (7.9%), compared with placebo,65 while with once-daily administration, the average HbA1c reduction was 0.6% relative to placebo (baseline 7.8%).66 Much less is known about the other inhibitors in clinical development, although all are said to have sustained anti-hyperglycemic efficacy.54,55,67 All these compounds appear well tolerated and seem to have neutral effects on body weight. 

Figure 2: Effects of 52 Weeks of Monotherapy with Vildagliptin on HbA1c Levels64

Efficacy as Combination Therapy
In a combination study with metformin, patients on placebo (metformin alone) showed a gradual deterioration in HbA1c levels (baseline, 7.9% rising to 8.3% by one year), whereas those also receiving twicedaily vildagliptin showed sustainable improvements, giving between-group differences of -0.7% at three months and -1.1% at one year. After one year, ~40% of patients receiving vildagliptin and metformin achieved HbA1c levels of <7%, compared with 10% of patients on metformin alone.68 With once-daily sitagliptin combined with metformin, HbA1c levels fell by 0.7% (baseline 8.0%), with 47% and 17% of patients achieving target levels of <7% and <6.5%, respectively, after 24 weeks, compared with no significant changes with metformin alone.69 In both studies,68,69 metformin treatment gave modest weight reductions, but this was unaffected by either inhibitor.

In a 28-day study, once daily vildagliptin was reported to give additional glycemic control when given in combination with pioglitazone, with the combination being well tolerated without need for dose adjustment of either compound.70 Similarly, sitagliptin, given once daily with pioglitazone for 24 weeks, reduced fasting glucose (by 1.0mmol/L) and HbA1c levels (by 0.9%; baseline, 8.1%), while there were no significant changes with pioglitazone alone.71 In this study, 45% and 24% of patients reached HbA1c levels <7% and 6.5%, respectively (compared with 23% and 5% on pioglitazone alone). The combination was generally well tolerated, but with a slightly higher incidence of gastrointestinal side effects. While pioglitazone caused a small weight gain, this was not affected by concomitant sitagliptin.71

A single study with vildagliptin (twice daily) as addon therapy to glimepiride gave additional reductions in HbA1c of 0.6% (baseline 8.5%) after 24 weeks, compared to a 0.1% increase for glimepiride alone.50 When vildagliptin was given twice daily together with existing insulin therapy, HbA1c levels decreased by a further 0.7% (baseline 8.5%) after 24 weeks, whereas they remained stable with insulin alone. Despite improved glycemic control, there were significantly fewer hypoglycemic events with the combination therapy.72Comparison with Existing Therapies
It is of considerable interest to know how effective DPP-4 inhibitors are compared with existing therapies. Treatment for one year with twice-daily vildagliptin or metformin monotherapy gave sustainable reductions in HbA1c levels (-1% and -1.4%, from baseline 8.7%), although the between-group difference failed to establish non-inferiority of vildagliptin to metformin (see Figure 2). There was no weight gain with vildagliptin (in contrast to modest weight loss with metformin), and while the overall incidence of side effects was similar, there were fewer gastrointestinal side effects with vildagliptin.64

Non-inferiority of vildagliptin to rosiglitazone was established in a 24-week study, with both treatments reducing mean HbA1c levels by 1.1% from baseline (8.7%). In a subset of patients (baseline HbA1c >9%), both drugs were equally effective (reductions of 1.8% (vildagliptin) and 1.9% (rosiglitazone)). Lipid profiles were improved more with vildagliptin, and in contrast to rosiglitazone, where patients gained weight, vildagliptin was weight neutral. The overall incidence of side effects was similar, although the incidence of edema with rosiglitazone was higher (4.9% versus 2.5%).73

In another study, sitagliptin was equally effective as glipizide when either agent was added to on-going metformin (mean HbA1c reductions of 0.7% from baseline, 7.5%), with greater red
ctions at higher baseline (~-0.2% from baseline <7%; ~-1.7% from baseline >9% in both groups). After one year, ~60% of patients in each group achieved target HbA1c levels of <7%, but the incidence of hypoglycemia was higher with glipizide (32%) than sitagliptin (5%).74

DPP-4 inhibitors have not yet been directly compared with the incretin mimetics. Exenatide entered the US market in June 2005 as add-on to existing therapy (metformin, sulfonylurea, or both), while liraglutide is in phase III trials. Combination therapy with exenatide lowers HbA1c levels by ~1.0% from baseline (8.4%) with 44% reaching 7% or below. Body weight is reduced, and both weight loss and glycemic improvements are sustained.75 Liraglutide monotherapy over 14 weeks also reduces HbA1c by up to 1.7% relative to placebo (baseline 8.1–8.5%), with ~50% achieving targets levels ≤7% (versus 8% on placebo). Body weight is also reduced.76Mechanism of Action
It appears that effects on both β- and α-cells contribute to the antidiabetic effects of DPP-4 inhibitors. Vildagliptin and sitagliptin treatment decreases proinsulin/insulin ratios reflecting improved β-cell function.77,78 The insulinogenic index, insulin sensitivity, and insulin secretory tone also all improve with vildagliptin (see Figure 3).68,79,80 

Figure 3: Effects of 52 Weeks Therapy with Vildagliptin as Add-on to Metformin on Insulin Secretion, Insulin Sensitivity, and Adaptation Index77

Copyright © 2005 American Diabetes Association, from Diabetes Care,Vol. 28, 2005;1936-40.77 Reprinted with permission from the American Diabetes Association.

Similar results are obtained with sitagliptin, demonstrating improvements in β-cell responsiveness to glucose both under fasting and post-prandial conditions.81 Glucagon levels are significantly reduced by vildagliptin,61,80,82 suggesting that glucagon suppression, leading to reduced hepatic glucose production, is an important mediator of the improvements in glucose tolerance. Indeed, when glucose metabolism was directly assessed in patients with T2DM, postprandial and fasting (overnight) endogenous glucose production was suppressed by vildagliptin, and was positively correlated with reductions in fasting plasma glucose.82Conclusions
DPP-4 inhibitors are a new class of oral anti-diabetic agents, which, in contrast to most existing antidiabetic agents, take advantage of several mechanisms of action. Both insulin secretion and biosynthesis are enhanced, while over-secretion of glucagon is suppressed, restoring the normal glucagon:insulin relationship, which is important for the regulation of hepatic glucose metabolism. As yet, β-cell trophic effects have only been demonstrated in animal and in vitro studies, but clinical studies have shown that β- cell function improves. However, it is still unknown how durable these β-cell effects are or whether they will overcome the gradual loss of functional β-cell mass, which is part of the natural progression of T2DM, to reduce the incidence or delay progression to secondary failure relative to other secretagogues. They target fasting and post-prandial glucose concentrations, both of which are believed to contribute to the development of many of the diabetic complications.

Although there may be subtle differences between the DPP-4 inhibitors in clinical development, at present there is apparently little to distinguish them in the clinic. With the exception of PSN9301, all are suitable for once-daily dosing.They seem likely to be as efficacious as currently available oral anti-diabetic agents, giving sustainable and clinically meaningful reductions in HbA1c levels, both as monotherapy and in combination with other anti-diabetic agents, and apparently can be used across a broad spectrum of patient groups (elderly; obese, poorly controlled diabetes; hepatic or renal failure).There are apparently no pharmacokinetic drug-drug interactions with other commonly prescribed agents, meaning that dose adjustments are unlikely to be needed. As a class, DPP-4 inhibitors appear to have an excellent safety profile, with little or no risk for hypoglycemia, no weight gain, and the potential benefit of addressing the islet dysfunction that characterizes T2DM.

2

References

  1. Holst JJ,“On the physiology of GIP and GLP-1”, Horm Metab Res (2004);36: pp. 747–754.
  2. Nauck MA,“Glucagon-like peptide 1 (GLP-1) in the treatment of diabetes”, Horm Metab Res (2004);36: pp. 852–858.
  3. Deacon CF, Holst JJ, “Dipeptidyl peptidase IV inhibitors: a promising new therapeutic approach for the management of type 2 diabetes”, Int J Biochem Cell Biol (2006);38: pp. 831–844.
  4. Deacon CF, Nauck MA,Toft-Nielsen M, et al.,“Both subcutaneously and intravenously administered glucagon-like peptide I are rapidly degraded from the NH2-terminus in type II diabetic patients and in healthy subjects”, Diabetes (1995);44: pp. 1126–1131.
  5. Del Prato S, Marchetti P, “Beta- and alpha-cell dysfunction in type 2 diabetes”, Horm Metab Res (2004);36: pp. 775–781.
  6. Holman RR, “Long-term efficacy of sulfonylureas: a United Kingdom Prospective Diabetes Study perspective”, Metabolism (2006);55(5 suppl. 1): pp. S2–S5.
  7. Butler AE, Janson J, Bonner-Weir S, et al., “Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes”, Diabetes (2003);52: pp. 102–110.
  8. Muscelli E, Mari A, Natali A, et al., “Impact of incretin hormones on β-cell function in subjects with normal or impaired glucose tolerance”, Am J Physiol Endocrinol Metab (2006);291: pp. E1144–E1150.
  9. Vaag AA, Holst JJ,Volund A, Beck-Nielsen HB,“Gut incretin hormones in identical twins discordant for non-insulin-dependent diabetes mellitus (NIDDM)—evidence for decreased glucagon-like peptide 1 secretion during oral glucose ingestion in NIDDM twins”, Eur J Endocrinol (1996);135: pp. 425–432.
  10. Chiasson JL, Rabasa-Lhoret R, “Prevention of type 2 diabetes. Insulin resistance and β-cell function”, Diabetes (2004);53(suppl. 3): pp. S34–S38.
  11. Holst JJ, Gromada J, “Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans”, Am J Physiol Endocrinol Metab (2004);287: pp. E199–E206.
  12. Stoffers DA, Kieffer TJ, Hussain MA, et al.,“Insulinotropic glucagon-like peptide 1 agonists stimulate expression of homeodomain protein IDX-1 and increase islet size in mouse pancreas”, Diabetes (2000);49: pp. 741–748.
  13. Xu G, Stoffers DA, Habener JF, Bonner-Weir S, “Exendin-4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats”, Diabetes (1999);48: pp. 2270–2276.
  14. Zhou J,Wang X, Pineyro MA, Egan JM, “Glucagon-like peptide 1 and exendin-4 convert pancreatic AR42J cells into glucagon- and insulin-producing cells”, Diabetes (1999);48: pp. 2358–2366.
  15. Urusova IA, Farilla L, Hui H, et al., “GLP-1 inhibition of pancreatic islet cell apoptosis”, Trends Endocrinol Metab (2004);15: pp. 27–33.
  16. Ørskov C, Holst JJ, Nielsen OV, “Effect of truncated glucagon-like peptide-1 [proglucagon-(78-107) amide] on endocrine secretion from pig pancreas, antrum, and nonantral stomach”, Endocrinology (1988);123: pp. 2009–2013.
  17. Nauck MA, Heimesaat MM, Behle K, et al.,“Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers”, J Clin Endocrinol Metab (2002);87: pp. 1239–1246.
  18. Wettergren A, Schjoldager B, Mortensen PE, et al., “Truncated GLP-1 (proglucagon 78-107-amide) inhibits gastric and pancreatic functions in man”, Dig Dis Sci (1993);38: pp. 665–673.
  19. Nauck MA, Niedereichholz U, Ettler R, et al.,“Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans”, Am J Physiol (1997);273: pp. E981–E988.
  20. Flint A, Raben A, Astrup A, Holst JJ, “Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans”, J Clin Invest (1998);101: pp. 515–520.
  21. Verdich C, Flint A, Gutzwiller JP, et al., “A meta-analysis of the effect of glucagon-like peptide-1 (7-36) amide on ad libitum energy intake in humans”, J Clin Endocrinol Metab (2001);86: pp. 4382–4389.
  22. Zander M, Madsbad S, Madsen JL, Holst J J, “Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study”, Lancet (2002);359: pp. 824–830.
  23. Nauck MA, Homberger E, Siegel EG, et al., “Incretin effects of increasing glucose loads in man calculated from venous insulin and c-peptide responses”, J Clin Endocrinol Metab (1986);63: pp. 492–498.
  24. Creutzfeldt W, “The incretin concept today”, Diabetologia (1979);16: pp. 75–85.
  25. Nauck M, Stockmann F, Ebert R, Creutzfeldt W, “Reduced incretin effect in type 2 (non-insulin-dependent) diabetes”, Diabetologia (1986);29: pp. 46–52.
  26. Toft-Nielsen MB, Damholt MB, Madsbad S, et al., “Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients”, J Clin Endocrinol Metab (2001);86: pp. 3717–3723.
  27. Vilsbøll T, Krarup T, Deacon CF, et al., “Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients”, Diabetes (2001);50: pp. 609–613.
  28. Kjems LL, Holst JJ,Volund A, Madsbad S, “The influence of GLP-1 on glucose-stimulated insulin secretion: effects on beta-cell sensitivity in type 2 and nondiabetic subjects”, Diabetes (2003);52: pp. 380–386.
  29. Vilsbøll T, Knop FK, Krarup T, et al.,“The pathophysiology of diabetes involves a defective amplification of the late-phase insulin response to glucose by glucose-dependent insulinotropic polypeptide-regardless of etiology and phenotype”, J Clin Endocrinol Metab (2003);88: pp. 4897–4903.
  30. Vilsbøll T, Holst JJ, “Incretins, insulin secretion and Type 2 diabetes mellitus”, Diabetologia (2004);47: pp. 357–366.
  31. Meier JJ, Nauck MA,“Incretins and the development of type 2 diabetes”, Curr Diabetes Rep (2006);6: pp. 194–201.
  32. Lambeir A-M, Durinx C, Scharpé S, De Meester I, “Dipeptidyl-peptidase IV from bench to bedside: an update on structural properties, functions, and clinical aspects of the enzyme DPPIV”, Critical Reviews in Clinical Laboratory Sciences (2003);40: pp. 209–294.
  33. Mentlein R, Gallwitz B, Schmidt WE,“Dipeptidyl peptidase IV hydrolyses gastric inhibitor peptide, glucagon-like peptide (7- 36) amide, peptide histidine methionine and is responsible for their degradation in human serum”, Eur J Biochem (1993);214: pp. 829–835.
  34. Deacon CF, Johnsen AH, Holst JJ, “Degradation of glucagon-like peptide-1 by human plasma in vitro yields an N-terminally truncated peptide which is a major endogenous metabolite in vivo”, J Clin Endocrin Metab (1995);80: pp. 952–957.
  35. Deacon CF, Nauck MA, Meier J, et al.,“Degradation of endogenous and exogenous gastric inhibitory polypeptide in healthy and in type 2 diabetic subjects as revealed using a new assay for the intact peptide”, J Clin Endocrinol Metab (2000);85: pp. 3575–3581.
  36. Deacon CF,Hughes TE, Holst JJ,“Dipeptidyl peptidase IV inhibition potentiates the insulinotropic effect of glucagon-like peptide- 1 in anesthetized pigs”, Diabetes (1998);47: pp. 764–769.
  37. Deacon CF, Danielsen P, Klarskov L, et al., “Dipeptidyl peptidase IV inhibition reduces the degradation and clearance of GIP and potentiates its insulinotropic and antihyperglycemic effects in anesthetized pigs”, Diabetes (2001);50: pp. 1588–1597.
  38. . Deacon CF,Wamberg S, Bie P, et al., “Preservation of active incretin hormones by inhibition of dipeptidyl peptidase IV suppresses meal-induced incretin secretion in dogs”, J Endocrinol (2002);172: pp. 355–362.
  39. Deacon CF, Pridal L, Klarskov L, et al., “Glucagon-like peptide-1 undergoes differential tissue-specific metabolism in the anesthetized pig”, Am J Physiol (1996);271: pp. E458–E464.
  40. Vilsbøll T, Agerso H, Krarup T, Holst JJ, “Similar elimination rates of glucagon-like peptide-1 in obese type 2 diabetic patients and healthy subjects”, J Clin Endocrinol Metab (2003);88: pp. 22022–22024.
  41. Deacon CF, Ahrén B, Holst JJ, “Inhibitors of dipeptidyl peptidase IV: a novel approach for the prevention and treatment of type 2 diabetes”, Expert Opin Investig Drugs (2004);13: pp. 1091–1102.
  42. Fleicher B,“CD26: a surface protease involved in T-cell activation”, Immunol Today (1994);15: pp. 180–184.
  43. Pederson RA, Kieffer TJ, Pauly R, et al., “The enteroinsular axis in dipeptidyl peptidase IV-negative rats”, Metabolism (1996);45: pp. 1335–1341.
  44. Marguet D, Baggio L, Kobayashi T, et al., “Enhanced insulin secretion and improved glucose tolerance in mice lacking CD26”, Proc Natl Acad Sci USA (2000);97: pp. 6874–6879.
  45. Lankas GR, Leiting B, Roy RS, et al., “Dipeptidyl peptidase IV inhibition for the treatment of type 2 diabetes: potential importance of selectivity over dipeptidyl peptidases 8 and 9”, Diabetes (2005);54: pp. 2988–2994.
  46. Vilsbøll T, Agersø A, Deacon CF, et al., “The elimination rates of intact GIP as well as its primary metabolite, GIP 3-42, are similar in type 2 diabetic patients and healthy subjects”, Regul Pept (2006);137: pp. 168–172.
  47. Mannucci E, Pala L, Ciani S, et al., “Hyperglycemia increases dipeptidyl peptidase IV activity in diabetes mellitus”, Diabetologia (2005);48: pp. 1168–1172.
  48. Ryskjaer J, Deacon CF, Carr RD, et al., “Plasma dipeptidyl peptidase-IV activity in patients with type-2 diabetes mellitus correlates positively with HbAlc levels, but is not acutely affected by food intake”, Eur J Endocrinol (2006);155: pp. 485–493.
  49. Holst JJ, Deacon CF, “Inhibition of the activity of dipeptidyl peptidase IV as a treatment for type 2 diabetes”, Diabetes (1998);47: pp. 1663–1670.
  50. Nathwani A,“The use of vildagliptin for treatment of patients with type 2 diabetes”, Late-breaking clinical studies; 66th Scientific Sessions, American Diabetes Association Annual Meeting; June 9-13, 2006: Washington, DC. Available at: http://webcasts.prous.com/ada2006_CME/article.asp?AID=164&CLID=2&CID=YY. Accessed November 2, 2006.
  51. Deacon CF,“MK-431 Merck”, Curr Opin Investigational Drugs (2005);6: pp. 419–426.
  52. Herman GA, Bergman A,Wagner JA,“Sitagliptin, a DPP-4 inhibitor: an overview of the pharmacokinetic (PK) profile and the propensity for drug-drug interactions (DDI)”, Diabetologia (2006);49(suppl. 1): p. 481 (Abstract).
  53. Augeri DJ, Robl JA, Betebenner DA, et al., “Discovery and preclinical profile of saxagliptin (BMS-477118): a highly potent, long-acting, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes”, J Med Chem (2005);48: pp. 5025–5037.
  54. GlaxoSmithKline. Corporate website.Available at: http://www.gsk.com. Accessed November 2, 2006.
  55. Rachman J, Jaehnig P, Golor G, et al.,“Glucose lowering effects and pharmakokinetics of 14-day treatment with the prandial DP-IV inhibitor, PSN9301, in patients with type 2 diabetes”, Diabetes (2006);55(suppl. 1): p. A130 (Abstract).
  56. Reimer MK, Holst JJ, Ahrén B, “Long-term inhibition of dipeptidyl peptidase IV improves glucose tolerance and preserves islet function in mice”, Eur J Endocrinol (2002);146: pp. 717–727.
  57. Pospisilik JA, Martin J, Doty T, et al., “Dipeptidyl peptidase IV inhibitor treatment stimulates beta-cell survival and islet neogenesis in streptozotocin-induced diabetic rats”, Diabetes (2003);52: pp. 741–750.
  58. Dutteroy A, Voelker F, Zhang X, et al., “The DPP-4 inhibitor vildagliptin increases pancreatic beta cell mass in rodents”, Diabetologia (2005);48(suppl. 1): p. A178 (Abstract).
  59. Mu J,Woods J, Zhou YP, et al.,“Chronic inhibition of dipeptidyl peptidase-4 with a sitagliptin analog preserves pancreatic {beta}- cell mass and function in a rodent model of type 2 diabetes”, Diabetes (2006);55: pp. 1695–1704.
  60. Ahrén B, Simonsson E, Larsson H, et al., “Inhibition of dipeptidyl peptidase IV improves metabolic control over a 4-week study period in type 2 diabetes”, Diabetes Care (2002);25: pp. 869–875.
  61. Ahrén B, Landin-Olsson M, Jansson P-A, et al., “Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and reduced glucagon levels in type 2 diabetes”, J Clin Endocrinol Metab (2004);89: pp. 2078–2084.
  62. Pratley RE, Jauffret-Kamel S, Galbreath E, Holmes D, “Twelve-week monotherapy with the DPP-4 inhibitor vildagliptin improves glycemic control in subjects with type 2 diabetes”, Horm Metab Res (2006);38: pp. 423–428.
  63. Ristic S, Byiers S, Foley J, Holmes D,“Improved glycaemic control with dipeptidyl peptidase-4 inhibition in patients with type 2 diabetes: vildagliptin (LAF237) dose response”, Diab Obes Metab (2005);7: pp. 692–698.
  64. Dejager S, Lebeaut A, Couturier A, Schweizer A,“Sustained reduction in HbA1c during one-year treatment with vildagliptin in patients with type 2 diabetes (T2DM)”, Diabetes (2006);55(suppl. 1): p. A29 (Abstract).
  65. Scott R, Herman G, Zhao P, et al., “Twelve-week efficacy and tolerability of MK-0431, a dipeptidyl peptidase IV (DPP-4) inhibitor, in the treatment of type 2 diabetes (T2D)”, Diabetes (2005);54(suppl. 1): p. A10 (Abstract).
  66. Herman G, Hanefeld M,Wu M, et al., “Effect of MK-0431 (sitagliptin), a dipeptidyl peptidase (DPP-4) inhibitor, on glycemic control after 12 weeks in patients with type 2 diabetes”, Diabetes (2005);54(suppl. 1): p. A134 (Abstract).
  67. Gregg RE, “Bristol-Myers Squibb Investors Community Meeting, November 2004”, Available at: http://www.bms.com/ investors/speeches_and_events/content/data/gregg.pdf. Accessed November 2, 2006,
  68. Ahrén B, Gomis R, Standl E, et al., “Twelve- and 52-week efficacy of the dipeptidyl peptidase IV inhibitor LAF237 in metformin-treated patients with type 2 diabetes”, Diabetes Care (2004);27: pp. 2874–2880.
  69. Karasik A, Charbonnel B, Liu J, et al., “Sitagliptin added to ongoing metformin therapy enhanced glycemic control and beta-cell function in patients with type 2 diabetes”, Diabetes (2006);55(suppl. 1): p. A119 (Abstract).
  70. Serra DB, He YL,Wang Y, et al., “Combination of the DPP-4 inhibitor vildagliptin (LAF237) with pioglitazone is safe and well tolerated with no pharmacokinetic interaction”, Diabetes (2005);54(suppl. 1): p. A528 (Abstract).
  71. Rosenstock J, Brazg R, Andryuk P, et al.,“Addition of sitagliptin to pioglitazone improved glycemic control with weight neutral effect over 24 weeks in inadequately controlled type 2 diabetes”, Diabetes (2006);55(suppl. 1): p. A132 (Abstract).
  72. Fonseca V, Dejager S, Albrecht D, et al., “Vildagliptin as add-on to insulin in patients with type 2 diabetes (T2DM)”, Diabetes (2006);55(suppl. 1): p. A111 (Abstract).
  73. Rosenstock J, Baron MA, Schweizer A, et al.,“Vildagliptin is as effective as rosiglitazone in lowering HbA1c but without weight gain in drug-naive patients with type 2 diabetes (T2DM)”, Diabetes (2006);55(suppl. 1): p. A133 (Abstract).
  74. Stein P, &ldquo
    Sitagliptin, a novel dipeptidyl peptidase-4 inhibitor, for the treatment of patients with type 2 diabetes”, Late-breaking clinical studies; 66th Scientific Sessions, American Diabetes Association Annual Meeting; June 9-13, 2006;Washington, DC. Available at: http://webcasts.prous.com/ada2006_CME/article.asp?AID=166&CLID=2&CID=YY. Accessed November 2, 2006.
  75. Riddle MC, Henry RR, Poon TH, et al.,“Exenatide elicits sustained glycaemic control and progressive reduction of body weight in patients with type 2 diabetes inadequately controlled by sulphonylureas with or without metformin”, Diabetes Metab Res Rev (2006);22: pp. 483–491.
  76. Vilsbøll T, Zdravkovic M, Le-Thi T, et al.,“Liraglutide significantly improves glycemic control and lowers body weight without risk of either major or minor hypoglycemic episodes in subjects with type 2 diabetes”, Diabetes (2006);55(suppl. 1): p.A27 (Abstract).
  77. Ahrén B, Pacini G, Foley JE, Schweizer A, “Improved meal-related beta-cell function and insulin sensitivity by the dipeptidyl peptidase-IV inhibitor vildagliptin in metformin-treated patients with type 2 diabetes over 1 year”, Diabetes (2005);28: pp. 1936–1940.
  78. Aschner P, Kipnes M, Lunceford J, et al., “Sitagliptin monotherapy improved glycaemic control in patients with type 2 diabetes”, Diabetologia (2006);49(suppl. 1): p. 5 (Abstract).
  79. Ahrén B, Pacini G, Foley JE, Schweizer A, “Improved meal-related beta-cell function and insulin sensitivity by the dipeptidyl peptidase-IV inhibitor vildagliptin in metformin-treated patients with type 2 diabetes over 1 year”, Diabetes Care (2005);28: pp. 1936–1940.
  80. Mari A, Sallas WM, He YL, et al., “Vildagliptin, a dipeptidyl peptidase IV-inhibitor improves model-assessed beta-cell function in patients with type 2 diabetes”, J Clin Endocrinol Metab (2005);90: pp. 4888–4894.
  81. Xu L, Dalla Man C, Cobelli C, et al., “Sitagliptin, a dipeptidyl peptidase-4 inhibitor, improved β-cell function in patients with type 2 diabetes: a model-based approach”, Diabetologia (2006);49(suppl. 1): p. 396 (Abstract).
  82. Balas B, Baig M,Watson C, et al.,“Vildagliptin suppresses endogenous glucose production (EGP) and increases beta cell function after single dose administration in type 2 diabetic (T2D) patients”, Diabetes (2006);55(suppl. 1): p. A29 (Abstract).
3

Further Resources

Share
Facebook
X (formerly Twitter)
LinkedIn
Via Email
Mark CompleteCompleted
BookmarkBookmarked
Copy LinkLink Copied
Stastical analysis indication diabetes mellitus .generative ai
5 mins

Trending Topic
Developed by Touch
Mark CompleteCompleted
BookmarkBookmarked

Forty-four Years of the UK Prospective Diabetes Study: Legacy Effect and Beyond

Saptarshi Bhattacharya, Sanjay Kalra, Lakshmi Nagendra

Very few trials in the history of medical science have altered the treatment landscape as profoundly as the UK Prospective Diabetes Study (UKPDS). Even 44 years after its inception, the trial and post-study follow-up findings continue to fascinate and enlighten the medical community. The study was conceived at a time when there was uncertainty about […]

touchREVIEWS in Endocrinology. 2024;21(1):1–2:Online ahead of journal publication
Advertisement
    • 4

    Related Content in Diabetes

    Latest articles videos and clinical updates - straight to your inbox

    Close Popup