This document summarizes a review article about the effects of Dipeptidyl Peptidase-4 (DPP-4) inhibitors on pancreatic islet cell function in patients with type 2 diabetes. DPP-4 inhibitors work by blocking the enzyme DPP-4, which degrades the incretin hormones GLP-1 and GIP. This allows GLP-1 and GIP levels to increase after meals and stimulate insulin secretion while decreasing glucagon secretion. Studies in rodents and humans suggest that DPP-4 inhibitors may improve beta cell and alpha cell function. However, there is currently no evidence that DPP-4 inhibitors can durably preserve islet cell function after treatment is stopped in humans. Large
A Study of Prescription Patterns of DPP-4 inhibitors..Samya Sayantan
Diabetes Mellitus (DM) is a metabolic disorder of which inappropriate hyperglycemia is the hallmark. For this reason, several classes of oral hypoglycemic drugs like Sulfonylurea, Biguanides, Meglitinides, Thiazolidinediones, α-glucosidase inhibitors are prescribed to treat Diabetes Mellitus. But at present Dipeptidyl Peptidase (DPP-4) Inhibitors have attracted attention as oral hypoglycemic agents that recently introduced to Bangladesh. This study aims to evaluate the current prescribing pattern of DPP-4 inhibitors at BIRDEM hospital, Bangldesh.during the survey, 150 prescriptions were collected and investigated where only 49% DPP-4 inhibitors – Sitagliptin, Linagliptin, Vildagliptin are prescribed even along with other conventional oral hypoglycemic drug. According to this survey, it is clear that Dipetidyl Peptidase (DPP-4) inhibitors is becoming more popular day by day in the management of hyperglycemia in Type-2 Diabetes without causing weight gain or hypoglycaemia in Bangladesh.
Teneligliptin the next generation gliptinAKSHATA RAO
Teneligliptin , one of the emerging gliptins have established its prowess among the gliptin giants like Sitagliptin Vildagliptin and Linagliptin. Proven to be safe in renally compromised patients, this one is to watch out for.
A Study of Prescription Patterns of DPP-4 inhibitors..Samya Sayantan
Diabetes Mellitus (DM) is a metabolic disorder of which inappropriate hyperglycemia is the hallmark. For this reason, several classes of oral hypoglycemic drugs like Sulfonylurea, Biguanides, Meglitinides, Thiazolidinediones, α-glucosidase inhibitors are prescribed to treat Diabetes Mellitus. But at present Dipeptidyl Peptidase (DPP-4) Inhibitors have attracted attention as oral hypoglycemic agents that recently introduced to Bangladesh. This study aims to evaluate the current prescribing pattern of DPP-4 inhibitors at BIRDEM hospital, Bangldesh.during the survey, 150 prescriptions were collected and investigated where only 49% DPP-4 inhibitors – Sitagliptin, Linagliptin, Vildagliptin are prescribed even along with other conventional oral hypoglycemic drug. According to this survey, it is clear that Dipetidyl Peptidase (DPP-4) inhibitors is becoming more popular day by day in the management of hyperglycemia in Type-2 Diabetes without causing weight gain or hypoglycaemia in Bangladesh.
Teneligliptin the next generation gliptinAKSHATA RAO
Teneligliptin , one of the emerging gliptins have established its prowess among the gliptin giants like Sitagliptin Vildagliptin and Linagliptin. Proven to be safe in renally compromised patients, this one is to watch out for.
Prospects of incretin mimetics in therapeuticsDr Sukanta sen
Comparative trials show that there are important differences between
and among the GLP-1 receptor agonists and DPP-4 inhibitors with
respect to glycemic lowering, weight effects, and effects on systolic
blood pressure and the lipid profile.
•Nausea, diarrhea, headaches, and dizziness are common with the
available GLP-1 receptor agonists.
•Upper respiratory tract infections, nasopharyngitis, and headaches
are common with the DPP-4 inhibitors.
•Ongoing safety evaluations should provide a clear picture regarding
long-term safety.
VILDAGLIPTIN: DPP-IV INHIBITOR
Generic name: Vildagliptin
Brand name: Galvus
Treatment for: type 2 diabetes
selective inhibitor of dipeptidyl-
peptidase IV (DPP-IV)
- the first in a new class of oral antidiabetic agents
- known as dipeptidyl peptidase IV inhibitors
(DPP-IV) inhibitors
International Journal of Pharmaceutical Science Invention (IJPSI)inventionjournals
International Journal of Pharmaceutical Science Invention (IJPSI) is an international journal intended for professionals and researchers in all fields of Pahrmaceutical Science. IJPSI publishes research articles and reviews within the whole field Pharmacy and Pharmaceutical Science, new teaching methods, assessment, validation and the impact of new technologies and it will continue to provide information on the latest trends and developments in this ever-expanding subject. The publications of papers are selected through double peer reviewed to ensure originality, relevance, and readability. The articles published in our journal can be accessed online.
Newer anti-hyperglycemic agents in type 2 diabetes mellitus - Expanding the h...Apollo Hospitals
Diabetes mellitus is a common, chronic and progressive disease resulting in micro and macrovascular complications. Many classes of drugs are available for treatment but still the search for newer anti-hyperglycemic agents continues to combat significant adverse effect profile, loss of efficacy, progressive nature of disease and improve patient compliance. New emerging therapies in pipeline include drugs targeting various pathophysiologic mechanisms like incretin based therapies, sodium glucose co-transporter inhibitors, glucokinase inhibitors, 11β hydroxy steroid dehydrogenase inhibitors, drugs modulating fatty acid metabolism, selective PPARγ receptor modulators and anti inflammatory agents. Aim of this review is to describe the emerging therapies for diabetes mellitus.
Newer Anti-Hyperglycemic agents in type 2 Diabetes Mellitus e Expanding the h...Apollo Hospitals
Diabetes mellitus is a common, chronic and progressive disease resulting in micro and macrovascular complications. Many classes of drugs are available for treatment but still the search for newer anti-hyperglycemic agents continues to combat significant adverse effect profile, loss of efficacy, progressive nature of disease and improve patient compliance. New emerging therapies in pipeline include drugs targeting various pathophysiologic mechanisms like incretin based therapies, sodium glucose co-transporter inhibitors, glucokinase inhibitors, 11b hydroxy steroid dehydrogenase inhibitors, drugs modulating fatty acid metabolism, selective PPARg receptor modulators and anti inflammatory agents.
Dipeptidyl peptidase inhibitors(DPP-IV): A deep insightRxVichuZ
This presentation deals with DPP-IV inhibitors, that are implicated for use in diabetes mellitus. Generalized pharmacology, including a precise insight into individual drugs have been elucidated.
This Presentation Give You A brief Information About DPP4 And New Recommendations .This Presentation Guide You How To Treat Patients With Safety.
For Further Contact:03354999496
O futuro na terapia baseada em incretins.Ruy Pantoja
Neste belo artigo realcei em amarelo as partes que mais me instigaram. Depois traço um paralelismo com a bela conferência do Prof. Buse, realizada em San Diego há um mês.
Prospects of incretin mimetics in therapeuticsDr Sukanta sen
Comparative trials show that there are important differences between
and among the GLP-1 receptor agonists and DPP-4 inhibitors with
respect to glycemic lowering, weight effects, and effects on systolic
blood pressure and the lipid profile.
•Nausea, diarrhea, headaches, and dizziness are common with the
available GLP-1 receptor agonists.
•Upper respiratory tract infections, nasopharyngitis, and headaches
are common with the DPP-4 inhibitors.
•Ongoing safety evaluations should provide a clear picture regarding
long-term safety.
VILDAGLIPTIN: DPP-IV INHIBITOR
Generic name: Vildagliptin
Brand name: Galvus
Treatment for: type 2 diabetes
selective inhibitor of dipeptidyl-
peptidase IV (DPP-IV)
- the first in a new class of oral antidiabetic agents
- known as dipeptidyl peptidase IV inhibitors
(DPP-IV) inhibitors
International Journal of Pharmaceutical Science Invention (IJPSI)inventionjournals
International Journal of Pharmaceutical Science Invention (IJPSI) is an international journal intended for professionals and researchers in all fields of Pahrmaceutical Science. IJPSI publishes research articles and reviews within the whole field Pharmacy and Pharmaceutical Science, new teaching methods, assessment, validation and the impact of new technologies and it will continue to provide information on the latest trends and developments in this ever-expanding subject. The publications of papers are selected through double peer reviewed to ensure originality, relevance, and readability. The articles published in our journal can be accessed online.
Newer anti-hyperglycemic agents in type 2 diabetes mellitus - Expanding the h...Apollo Hospitals
Diabetes mellitus is a common, chronic and progressive disease resulting in micro and macrovascular complications. Many classes of drugs are available for treatment but still the search for newer anti-hyperglycemic agents continues to combat significant adverse effect profile, loss of efficacy, progressive nature of disease and improve patient compliance. New emerging therapies in pipeline include drugs targeting various pathophysiologic mechanisms like incretin based therapies, sodium glucose co-transporter inhibitors, glucokinase inhibitors, 11β hydroxy steroid dehydrogenase inhibitors, drugs modulating fatty acid metabolism, selective PPARγ receptor modulators and anti inflammatory agents. Aim of this review is to describe the emerging therapies for diabetes mellitus.
Newer Anti-Hyperglycemic agents in type 2 Diabetes Mellitus e Expanding the h...Apollo Hospitals
Diabetes mellitus is a common, chronic and progressive disease resulting in micro and macrovascular complications. Many classes of drugs are available for treatment but still the search for newer anti-hyperglycemic agents continues to combat significant adverse effect profile, loss of efficacy, progressive nature of disease and improve patient compliance. New emerging therapies in pipeline include drugs targeting various pathophysiologic mechanisms like incretin based therapies, sodium glucose co-transporter inhibitors, glucokinase inhibitors, 11b hydroxy steroid dehydrogenase inhibitors, drugs modulating fatty acid metabolism, selective PPARg receptor modulators and anti inflammatory agents.
Dipeptidyl peptidase inhibitors(DPP-IV): A deep insightRxVichuZ
This presentation deals with DPP-IV inhibitors, that are implicated for use in diabetes mellitus. Generalized pharmacology, including a precise insight into individual drugs have been elucidated.
This Presentation Give You A brief Information About DPP4 And New Recommendations .This Presentation Guide You How To Treat Patients With Safety.
For Further Contact:03354999496
O futuro na terapia baseada em incretins.Ruy Pantoja
Neste belo artigo realcei em amarelo as partes que mais me instigaram. Depois traço um paralelismo com a bela conferência do Prof. Buse, realizada em San Diego há um mês.
This prsentation explains the use of biomarker with reference to an article: Accelerating Drug Develeopment using Biomarkers-Sitagliptin.
It was presented my my 2 friends and me. Hope it helps you guys.
Anti ulcer drugs and their Advance pharmacology ||
Anti-ulcer drugs are medications used to prevent and treat ulcers in the stomach and upper part of the small intestine (duodenal ulcers). These ulcers are often caused by an imbalance between stomach acid and the mucosal lining, which protects the stomach lining.
||Scope: Overview of various classes of anti-ulcer drugs, their mechanisms of action, indications, side effects, and clinical considerations.
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
Pulmonary Thromboembolism - etilogy, types, medical- Surgical and nursing man...VarunMahajani
Disruption of blood supply to lung alveoli due to blockage of one or more pulmonary blood vessels is called as Pulmonary thromboembolism. In this presentation we will discuss its causes, types and its management in depth.
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
1. Dipeptidyl Peptidase-4 Inhibitors and Preservation of Pancreatic Islet-Cell Function: A
Critical Appraisal of the Evidence
R.E. van Genugten, D.H. van Raalte, M. Diamant
Diabetes Center, Department of Internal Medicine, VU University Medical Center,
Amsterdam, The Netherlands
Corresponding author R.E. van Genugten, MD, Diabetes Center, Dpt. of Internal Medicine,
VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands,
PO Box 7057. Tel: +31 20 444 2264, Fax: +31 20 444 3349, E-mail: r.vangenugten@vumc.nl
Manuscript word count: 5305
Abstract word count: 220
Number of tables: 6
Keywords type 2 diabetes, incretins, GLP-1, GIP, beta cell, beta-cell mass, alpha cell,
sitagliptin, vildagliptin, saxagliptin, alogliptin, linagliptin
Disclosure statement RvG and DvR declare no conflict of interest. Through MD, the VU
University Medical Center received research grants from Amylin, Eli Lilly, Glaxo Smith
Kline, Merck, Novartis, Novo Nordisk, Sanofi Aventis and Takeda, consultancy fee from Eli
Lilly, Merck, Novo Nordisk, Sanofi Aventis and speaker fee from Eli Lilly, Merck and Novo
Nordisk.
Acknowledgements RvG is supported by the EFSD/MSD clinical research programme 2008
and DvR is supported by the Dutch Top Institute Pharma (TIP) grant T1-106.
This is an Accepted Article that has been peer-reviewed and approved for publication in the Diabetes,
Obesity and Metabolism, but has yet to undergo copy-editing and proof correction. Please cite this
article as an "Accepted Article"; doi: 10.1111/j.1463-1326.2011.01473.x
1
2. Abstract
Type 2 diabetes mellitus (T2DM) develops as a consequence of progressive beta-cell
dysfunction in the presence of insulin resistance. None of the currently-available T2DM
therapies is able to change the course of the disease by halting the relentless decline in
pancreatic islet cell function. Recently, dipeptidyl peptidase (DPP)-4 inhibitors, or incretin
enhancers, have been introduced in the treatment of T2DM. This class of glucose-lowering
agents enhances endogenous glucagon-like peptide 1 (GLP-1) and glucose-dependent
insulinotropic polypeptide (GIP) levels by blocking the incretin-degrading enzyme DPP-4.
DPP-4 inhibitors may restore the deranged islet-cell balance in T2DM, by stimulating meal-
related insulin secretion and by decreasing postprandial glucagon levels. Moreover, in rodent
studies, DPP-4 inhibitors demonstrated beneficial effects on (functional) beta-cell mass and
pancreatic insulin content. Studies in humans with T2DM have indicated improvement of
islet-cell function, both in the fasted state and under postprandial conditions and these
beneficial effects were sustained in studies with a duration up to two years. However, there is
at present no evidence in humans to suggest that DPP-4 inhibitors have durable effects on
beta-cell function after cessation of therapy. Long-term, large-sized trials using an active
blood glucose lowering comparator followed by a sufficiently long washout period after
discontinuation of the study drug are needed to assess whether DPP-4 inhibitors may durably
preserve pancreatic islet-cell function in patients with T2DM.
2
3. Introduction
Prevention and treatment of type 2 diabetes mellitus (T2DM) and its complications are
worldwide major health care issues given the alarming global increase in the prevalence of
T2DM due to the obesity pandemic [1]. Abdominal obesity and hepatic steatosis decrease
peripheral and hepatic insulin sensitivity. Under normal circumstances, pancreatic beta cells
compensate for this reduced insulin sensitivity by enhancing insulin secretion. However, in
susceptible individuals, this compensatory response is hampered by incipient beta-cell
dysfunction resulting in a gradual rise in blood glucose concentrations and finally, the
development of T2DM [2]. Beta-cell dysfunction is not only a prerequisite for the
development of T2DM, but, due to its progressive nature, it additionally determines the
progressive course of the disease. Accordingly, T2DM is characterised by progressive loss of
glycaemic control and increased need for multiple therapies to sustain normoglycaemia [3]. In
the United Kingdom Prospective Diabetes Study (UKPDS) the decline of pancreatic beta-cell
function in newly diagnosed patients with T2DM was estimated to occur at an annual rate of
approximately 4% [3]. In addition to loss of beta-cell function, autopsy studies have shown
that patients with T2DM have decreased beta-cell mass as compared to age- and BMI-
matched non-diabetic individuals [4]. Thus, it is likely that both reduced number of beta-cells
and impaired beta-cell function, leading to a diminished functional islet mass, contribute to
the development and subsequently, the progressive course of T2DM. More recently, reduced
inhibition of glucagon-secreting alpha-cells has also been identified to contribute to
hyperglycaemia in T2DM, since glucagon stimulates hepatic glucose production [5]. Hence,
in patients with T2DM, functional pancreatic islet-cell balance is impaired resulting in
chronic hyperglycaemia. A major challenge in the treatment of T2DM is to identify a
therapeutic agent that can alter the course of the disease by preventing this gradual decline in
pancreatic islet-cell function and diminution of beta-cell mass. Current T2DM treatment
options, most notably metformin and the sulfonylurea derivatives, fail in this regard, since
glycaemic control deteriorates over time despite treatment with these drugs [3,6]. Eventually,
almost all patients with T2DM will require insulin replacement therapy.
In recent years, a new class of glucose-lowering medication based on incretin
hormones, glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide
(GIP), has been introduced for the treatment of T2DM. These compounds enhance the so-
called incretin effect, i.e. the phenomenon that following oral ingestion of glucose, due to the
secretion of the gut-derived incretin hormones, the increase in plasma insulin response is two
to three fold greater than is the case when the same level of hyperglycaemia is produced by
3
4. intravenous administration of glucose [7]. Incretin-enhancers or dipeptidyl peptidase (DPP)-4
inhibitors inhibit the incretin-degrading enzyme DPP-4 that is ubiquitously present, thereby
increasing the bio-availability of active GLP-1 and GIP which results in enhanced meal-
related insulin secretion. In addition, DPP-4 inhibitors lower postprandial glucagon responses
and thus may restore functional islet cell balance. In this review we will discuss the evidence
that DPP-4 inhibitors improve both beta-cell and alpha-cell function. We will discuss
preclinical data and subsequently address the effects of all currently-available DPP-4
inhibitors on fasting and dynamic measures of islet cell function as reported in randomised
clinical trials in humans (last PUBMED search 1-Apr-2011). Finally, based on the current
evidence, we will discuss the potential of these agents to durably enhance islet-cell function in
patients with T2DM and modify the progressive course of the disease.
DPP-4 inhibitors: mode of action and clinical efficacy
The incretin hormones GLP-1 and GIP are secreted from the small intestine directly in
response to food intake and stimulate postprandial glucose-dependent insulin secretion. In
recent years several studies have unravelled the pathways via which GLP-1 and GIP increase
postprandial insulin secretion [8]. GLP-1 and GIP receptors are present on pancreatic beta
cells via which the incretin hormones directly enhance insulin secretion from insulin
containing granules. However, the most important contributor may be GLP-1’s effect on
afferent nerves in the intestinal mucosa or portal vein [9,10], since less than 25% of the active
metabolite eventually reaches the pancreatic islets, due to direct cleavage by the enzyme DPP-
4 upon secretion from the L-cells located in the gut [11]. Furthermore GLP-1 lowers glucagon
secretion mainly indirectly via somatostatin, in addition to a proposed direct inhibition
through GLP-1 receptors on the alpha cells. Although GLP-1-stimulated insulin secretion
from the beta-cell is also believed to contribute to the indirect route by which GLP-1
decreases glucagon, studies in T1DM patients who had no residual beta-cell function also
showed decreased (postprandial) glucagon secretion [12,13], arguing against an important
role of insulin secretion in GLP-1’s effect on glucagon. GIP, however, exerts a
glucagonotropic effect in the euglycaemic state [14]. In addition, evidence exists from
preclinical studies that incretins also replenish insulin stores and may promote beta-cell mass
by increasing beta-cell proliferation and reducing apoptosis [8,15].
Endogenous GLP-1 and GIP are not suitable for therapeutic use in humans, since
directly upon secretion, both GLP-1 and GIP are cleaved by the enzyme DPP-4, resulting in
an active plasma half-life time of just several minutes and thus necessitating continuous
4
5. parenteral administration [16]. DPP-4 inhibitors increase endogenous circulating levels of
active GLP-1 and GIP by blocking the incretin-degrading enzyme DPP-4 and thereby
approximately double postprandial active, i.e. non-degraded, incretin levels [17]. The extent
to which other DPP-4 substrates, such as glucagon-like peptide-2, peptide YY [18], gastrin
releasing peptide or pituitary adenylate cyclase activating polypeptide (PACAP) [19],
contribute to the glucose-lowering effect in vivo remains at present unclear.
Treatment of patients with T2DM with DPP-4 inhibitors as monotherapy has shown
beneficial effects on glycaemic control as measured by haemoglobin A1c (HbA1c) levels,
compared to placebo: mean change in HbA1c as compared to placebo ranged from -0.67% to
-0.79% (-9 to -7 mmol/mol); P <0.001 [20]. DPP-4 inhibitors can be administered orally, once
or twice daily. Currently, the DPP-4 inhibitors sitagliptin and saxagliptin are approved by
both the US Food and Drug Administration (FDA) and European Medicines Agency (EMA)
for use as monotherapy (sitagliptin only) or as add-on to other glucose-lowering medication in
the treatment of T2DM. Vildagliptin is approved for the European market only as add-on and
alogliptin is currently approved for the Japanese market and awaiting approval by EMA and
FDA. The approval of linagliptin is currently pending, while several other companies have
DPP-4 inhibitors still under development.
DPP-4 inhibition improves pancreatic islet-cell function: preclinical data
Administration of DPP-4 inhibitors to several rodent models of diabetes (e.g. high-fat diet-
induced and/or streptozotocin (STZ)-induced diabetes) resulted in improved fasting and non-
fasting glucose control, together with enhanced plasma insulin levels, reduced plasma
glucagon levels and increased pancreatic insulin content (summarised in Table 1) [21-35].
However, in addition to the use of different rodent models, these studies use diverse methods
in order to describe glucose metabolism and pancreatic function, which potentially hampers
comparison.
Flock et al. demonstrated the necessity of the presence of functional incretin receptors on islet
cells for the glucoregulatory effect of DPP-4 inhibitors in dual incretin-receptor knock-out
(DIRKO) mice. In these mice, DPP-4 inhibitor treatment did not exert any favourable effect,
whereas in wild type mice DPP-4 inhibition resulted in improved glycaemic control [26]. The
beneficial effects of DPP-4 treatment on fasting and non-fasting glycaemic control remained
present during chronic treatment (up to three months) (Table 1). Moreover, when compared to
conventional therapy, the sulphonylurea (SU) agent glipizide, DPP-4 inhibitor treatment
resulted in prolonged improvement in glycaemic control over ten weeks, whereas in the
5
6. glipizide-treated mice glycaemic control deteriorated after approximately five weeks despite
ongoing treatment [25,32].
Several studies have assessed the effects of acute and chronic treatment with DPP-4
inhibitors on pancreatic islet morphology and beta-cell mass in rodents (Table 1). Chronic
DPP-4 inhibitor treatment (two to three months) was demonstrated to increase beta-cell mass
by promoting cell proliferation and reducing apoptosis [24,25,29]. Interestingly, after a
twelve-day drug washout period, durable beneficial effects on beta-cell mass, i.e. enhanced
beta-cell replication and reduced apoptosis, were seen in neonatal rats treated with a DPP-4
inhibitor for nineteen days [35]. In contrast, other studies showed no effect of treatment with
DPP-4 inhibitors on total beta-cell mass [21,23,28,34], however in various studies a beneficial
effect on the intra-islet distribution pattern of alpha and beta cells was shown [27,32]. In
addition, DPP-4 inhibition demonstrated durable effects on pancreatic islet mass and/or
insulin content while this effect was not seen by SU [32]. Furthermore, combination treatment
of a DPP-4 inhibitor with either the thiazolidinedione (TZD) pioglitazone [31] or the alpha-
glucosidase inhibitor voglibose [34], resulted in increased pancreatic insulin content,
compared to either agent alone.
To summarise, in various animal models, DPP-4 inhibitors improved glucose
tolerance, by enhancing insulin secretion and reducing glucagon secretion and this effect
outlasted the action of the presently used blood-glucose lowering agents, most particularly
SU. Since DPP-4 inhibitors also stimulated insulin production, increased beta-cell mass and
restored pancreatic islet topography in these rodent models, DPP-4 inhibition holds a promise
as therapeutical option with regard to preservation of beta-cell function also in humans with
T2DM.
DPP-4 inhibition and pancreatic beta-cell function: clinical data
Measures of beta-cell function in humans
Pancreatic beta-cell function involves many different aspects, including glucose and nutrient
sensing, insulin secretion and production following stimulation by different secretagogues and
pro-insulin to insulin processing. Therefore, any test performed, and any variable derived
thereof, has limitations and should be regarded as mere surrogate estimate. Also, irrespective
of the actual test performed it is always important to keep in mind that insulin secretion
responses should be interpreted in the context of prevailing insulin sensitivity and glucose
level [2]. As such, an identical insulin response before and following an intervention that
reduces blood glucose and body weight, may still designate an improvement when taking into
6
7. account the glucose and body weight changes.
In humans, the various aspects of beta-cell function can be assessed by several
methods including static and dynamic measurements. The most widely used estimates are the
static or fasting measures, including the homeostatic model assessment beta-cell function
index (HOMA-B) [36] and the pro-insulin to insulin (PI/I) ratio [37]. However, the value of
fasting measures of beta-cell function is limited, since beta cells are mostly active in the
postprandial and hyperglycaemic state. Dynamic measures may therefore be more appropriate
to quantify beta-cell function. As such, many studies have calculated parameters of beta-cell
function from intravenous glucose challenge tests, oral glucose tolerance tests or standardized
mixed meal tests. Typical beta-cell measurements derived from oral glucose load tests include
the postprandial insulin area under the curve (AUC) corrected for glucose AUC
(AUCinsulin/glucose), which measures insulin secretion during the total postprandial period, and
the insulinogenic index (IGI), a measure of early phase insulin secretion (i.e. insulin secretion
during the first 30 minutes after meal ingestion corrected for glucose). In addition,
mathematical models have been developed to describe postprandial beta-cell function
[38,38,39]. These models describe different aspects of the insulin secretory function.
Furthermore, dynamic measures of beta-cell function may be assessed from the
intravenous glucose tolerance test (IVGTT) or the hyperglycaemic (arginine-stimulated)
clamp method. Although the hyperglycaemic clamp test, due to its high reproducibility, is
currently regarded as the gold standard for assessing pancreatic beta-cell function, it is a non-
physiological test since glucose consumption does not normally occur via the intravenous
route, and additionally, its use is limited for routine measurements due to the demands
imposed on the patient and the associated high cost.
In the sections below, we will present the results of clinical trials using DPP-4
inhibition in patients with T2DM and subjects with pre-diabetes, i.e. impaired glucose
metabolism, with regard to aforementioned static and dynamic parameters of beta-cell
function.
Effect of DPP-4 inhibitors on static measures of beta-cell function
DPP-4 inhibitor monotherapy was shown to improve fasting measures of beta-cell function,
including HOMA-B and PI/I ratio, in clinical trials in (drug-naïve) patients with T2DM
(Table 2) [40-50]. Concerning HOMA-B, trials of 12 to 26 week duration demonstrated an
increase within the range of 5.1% to 26.8 % following monotherapy with either sitagliptin,
vildagliptin, alogliptin, saxagliptin or linagliptin compared to placebo treatment (Table 2).
7
8. Furthermore, PI/I ratio improved by treatment with all DPP-4 inhibitors given as
monotherapy relative to placebo: 24-26 week active treatment with either sitagliptin,
vildagliptin, alogliptin or linagliptin resulted in a decrease of PI/I ratio ranging from 0.04 to
0.12 (Table 2) [40,41,46,47,50].
When used as add-on therapy to other oral blood glucose-lowering agents such as
metformin, SU derivates or TZDs, DPP-4 inhibition exerted an additional beneficial effect on
these fasting parameters of beta-cell function in most studies (Table 3) [43,51-64]. DPP-4
inhibition as add-on to metformin improved static measures of beta-cell function comparable
to other glucose lowering agents as add-on to metformin, e.g. TZD [55] and SU, the latter
with regard to PI/I ratio only [54,56]. DPP-4 inhibitors as add-on to either SU [61], TZDs
[62,64] or metformin/SU combination therapy [60], similarly affected static parameters of
beta-cell function beneficially compared to placebo.
Effect of DPP-4 inhibitors on dynamic measures of beta-cell function
Postprandial parameters of beta-cell function Clinical trials that assessed the effect of DPP-4
inhibitors on beta-cell function measurements derived from standardised mixed-meal tests or
oral glucose tolerance tests are presented in Table 4 (monotherapy) [17,40,41,44,46,49,50,65-
73] and table 5 (combination treatment) [43,51-53,56,59,60,63,64,74-79].
The early beta-cell response, calculated as IGI, was improved by DPP-4 inhibition in
several trials in which monotherapy up to one year was assessed (approximate mean increase
of 38%) [44,46,49,67]. Saxagliptin as add-on to TZD resulted in increased IGI compared to
placebo as add-on to TZD after 24 weeks treatment (up to 150 % increase compared to
placebo) [64]. Postprandial AUCinsulin/glucose, was improved by both sitagliptin [40,41,44] and
vildagliptin [46,66,67,70] with an increase compared to placebo ranging from 15.1% to
38.6%. Drug-naïve diabetic patients with mild hyperglycaemia, i.e. HbA1c < 7.5% (58
mmol/mol), benefited from one year DPP-4 inhibitor treatment as well according to an
increase of 14.4% (P<0.001) in AUCinsulin/glucose [67] (Table 4). In addition, a beneficial effect
was also present in subjects at risk to develop T2DM, i.e. subjects with impaired fasting
glucose (IFG) and/or impaired glucose tolerance (IGT) [72,73]. DPP-4 inhibitors as add-on to
either metformin [51], SU [61] or metformin/SU [60] showed after 24 weeks treatment an
increase in AUCinsulin/glucose ratio within a range of 22.7% to 28.8%. In contrast, Retnakaran et
al., did not show different results for AUCinsulin/glucose (corrected for insulin resistance)
following 48 weeks sitagliptin treatment compared to placebo as add-on to metformin
(decrements in beta-cell function were 16.1 % and 31.7 % respectively; p=0.23). However,
8
9. this intervention was preceded by a four-week intensive insulin treatment period which could
have outweighed the effects of DPP-4 inhibition [53].
Mathematical modelling of postprandial beta-cell function DPP-4 inhibitors improved
several model-derived parameters of beta-cell function. The model-based approach developed
by Mari et al. was used to assess beta-cell function after one year treatment with vildagliptin
50 mg QD in drug-naïve patients with T2DM. Several model-derived parameters of beta-cell
function improved significantly (insulin secretory rate by 17%, P<0.001; glucose sensitivity
of the beta-cell by 40%, P<0.001) [66]. This effect was shown for insulin secretory rate after
both four weeks of treatment (P<0.005) [80] and acute treatment (P<0.04) [81]. Based on
Cobelli’s model, Φtotal increased by 19.1% (P<0.05) and Φs almost doubled (93% increase;
P<0.05) after 24 weeks sitagliptin compared to placebo as add-on to metformin [82]. A
similar positive effect was seen in studies of shorter duration [69,71,83].
Parameters of beta-cell function derived from intravenous glucose studies Aaboe et al. [84]
investigated the effect of sitagliptin 100 mg QD after twelve weeks of treatment on
hyperglycaemic and arginine-stimulated clamp-derived parameters of beta-cell function in 24
patients with T2DM treated with metformin. With blood-glucose targeted at 20 mM, first-
phase insulin secretion, second-phase insulin secretion and arginine-stimulated insulin
secretion were increased, compared to placebo treatment. In accordance, Bunck et al. [85]
reported significantly improved clamp-derived beta-cell function parameters after one year
treatment with vildagliptin 100 mg QD in drug-naïve diabetic patients with mild
hyperglycaemia. Additionally, in patients with T2DM on metformin or diet, 12-week
vildagliptin treatment resulted in an increase in acute insulin response to intravenous glucose
(AIRg) of 50% (P=0.033) [86]. Utzschneider et al. investigated the effect of a six week
vildagliptin treatment during an intravenous glucose tolerance test in IFG subjects at high risk
for developing diabetes, and demonstrated in this population similarly an enhanced acute
insulin secretion (AIRg +27%, P<0.05) [72].
DPP-4 inhibition and pancreatic alpha-cell function: clinical data
Failure to suppress glucagon secretion under hyperglycaemic conditions is an important
feature of T2DM [5]. Several short- and long-term trials showed beneficial effects of DPP-4
inhibitors on postprandial glucagon excursions [49,64,65,69-71,73,77] (Table 4&5). With
regard to other glucose-lowering agents, the significantly reduced postprandial AUCglucagon
resulting from 24-week saxagliptin treatment, tended to surpass that of TZD treatment alone
(P=0.072) [64]. In subjects with impaired glucose metabolism there was no effect on
9
10. postprandial AUCglucagon after a six week treatment with vildagliptin [72], although a twelve-
week treatment in a larger cohort of subjects at risk to develop T2DM did show a small but
significant decrease in glucagon levels (-7.6% compared to placebo, P=0.007) [73].
Furthermore, in a four week cross-over study, comparing vildagliptin 100 mg QD to placebo,
alpha-cell function was assessed both postprandially and during a stepped hyperinsulinaemic-
hypoglycaemic clamp. In accordance with other studies, postprandial AUCglucagon decreased
significantly by 9.7%. Moreover, during hypoglycaemia, the glucagon-lowering effect of
DPP-4 inhibition was attenuated [70]. The finding that DPP-4 inhibitors affect glucagon
levels dependent of prevailing blood glucose levels is clinically important given previous
concerns regarding these agents and their effect on the glucagon response to hypoglycaemia.
In fact, the above-described data suggest that DPP-4 inhibitors may even decrease the risk of
hypoglycaemia [70].
Long-term effects of DPP-4 inhibition on pancreatic islet cell function: clinical data
Since most clinical (registration) trials to date are designed to last up to approximately six
months, there is little information concerning long-term effects of DPP-4 inhibition on
pancreatic islet-cell function in humans. Although the duration of the majority of randomised
clinical trials (RCT) was prolonged by an extension period, mostly up to two years, it is likely
that only those patients who showed response to DPP-4 therapy, or otherwise profited from
the intervention, consented to continue in the trial. Conversely, those who had loss of
glycaemic control were not enrolled in the extension part of the RCT. These patients had
either progression of beta-cell function deterioration or may have already been non-
responders to DPP-4 inhibition at the onset of the study. Therefore, data from extended trials
should be carefully interpreted.
Stable beneficial effects on PI/I ratio [57] or both PI/I ratio and HOMA-B [54] were
shown during a one year treatment with vildagliptin or sitagliptin, respectively, as add-on to
metformin. Also after two years of treatment, beneficial effect of sitagliptin on fasting beta-
cell function was demonstrated; and this effect was larger compared to that reached when SU
was used as add-on to metformin [56]. Accordingly, a beneficial effect on dynamic
parameters of beta-cell function was visible after one year treatment with vildagliptin as add-
on to metformin, demonstrated by a 72.3% increase in AUCinsulin/glucose, whereas this
parameter deteriorated by 24.5% in the placebo-treated group [74]. Moreover, in another
study with treatment duration of two years, vildagliptin did show a stabilization of beta-cell
function, in contrast to the deterioration seen in the placebo-treated group [68]. In addition,
10
11. two years of sitagliptin as add-on to metformin significantly improved beta-cell function
which persisted after a wash-out period of four to seven days (AUCinsulin/glucose +8.9%
compared to baseline) [56]. However, in studies lasting one year, after a four week wash-out
period the beneficial effect on beta-cell function did not sustain [67,74]. Similarly, in studies
that assessed dynamic beta-cell function by intravenous glucose challenge tests, lasting six
weeks [72], twelve weeks [86] or 52 weeks [85], beta-cell function parameters returned back
to baseline values after the washout period of two weeks (for the first two studies) and twelve
weeks (for the latter study). Concerning pancreatic alpha-cell function, two year treatment
with vildagliptin 50 mg BID as add-on to metformin improved postprandial glucagon
suppression compared to the use of a SU as add-on to metformin [77]. No data about
persistence of effects on glucagon secretion following an off-drug period are available.
In conclusion, the available data indicate that DPP-4 inhibitors show stable
improvements in beta-cell function parameters after chronic treatment up to two years in
open-label extension trials, however, there is at present no direct evidence to suggest that
DPP-4 inhibitors have durable effects on beta-cell function after cessation of therapy. Thus, it
is presently unknown whether these agents can modify the progressive course of T2DM.
Summary and discussion
In summary, preclinical studies have demonstrated beneficial effects of DPP-4 inhibition on
pancreatic islet-cell function. This was concluded from studies in different rodent models of
hyperglycaemia and diabetes showing improved insulin secretion, increased beta-cell mass
and proliferation, and suppression of glucagon secretion under hyperglycaemic conditions. In
humans, DPP-4 inhibitors improved fasting and dynamic beta-cell function measures
including HOMA-B, PI/I ratio, IGI, AUCinsulin/glucose ratio and model-derived parameters
obtained during oral glucose challenge tests. Moreover, glucose- and arginine-stimulated
insulin secretion, assessed by the hyperglycaemic clamp method, were improved by DPP-4
inhibition (Table 6). Finally, postprandial glucagon excursion decreased during DPP-4
inhibitor treatment. These improvements in islet-cell function clinically result in HbA1c
reduction, and data from animal studies possibly suggest sustained effects on islet-cell
function. However, several important considerations regarding DPP-4 inhibition and the
effect on pancreatic islet-cell function should be addressed.
Firstly, given the many different tests performed and variables reported to assess
changes in beta-cell function after intervention with incretin-based therapies in the various
human studies, the size of the effects is difficult to compare. In particular, it is impossible to
11
12. reliably compare the effects of the different agents from data obtained from separate versus
head-to-head comparison studies, however, we attempted to fully outline the currently
available data and to compare when possible.
Secondly, aetiology and course of T2DM in rodents is different from that in humans
and although rodent studies reported improved glycaemic control together with positive
effects on beta-cell mass and morphology, in humans such durable effects have not (yet) been
demonstrated after chronic treatment with DPP-4 inhibitors. Indeed, whether the beneficial
effects that are observed in clinical trials up to two years remain after drug-washout, is still
inconclusive (Table 6) since few studies reported off-drug values of beta-cell function of
which only one showed durable effects measured four to seven days after cessation of therapy
[56], whereas in others after cessation of minimally four weeks, no positive effects were
observed any longer [67,72,74,85,86]. Moreover, most long-term studies were extension
studies from original six-month trials, therefore it is possible that only patients that responded
well to the intervention consented to continue in the trial whereas the non-responders declined
enrollment in the extension. It would be of interest, to compare the (long-term) responders to
those who dropped out due to disease progression in order to identify possible determinants or
predictors of response to incretin-based therapy, such as disease duration at onset of therapy,
baseline beta-cell function or genetic determinants such as GLP-1 receptor polymorphism.
Additionally, since beta-cell function declines gradually over years, the possible beta-cell
sparing effect of a therapeutic agent should be assessed after substantially long-term treatment
of years. Indeed, since in the UKPDS [3] and ADOPT (A Diabetes Outcome Progression
Trial) [87] studies, beta-cell function improved initially but over time a decline was found, too
short observations may yield erroneous results. Therefore longer term studies with a duration
of at least five, but preferably more years using gold-standard methodology for reproducible
repetitive beta-cell function assessment and including a drug-washout period, should be
carried out in order to assess the full potential of DPP-4 inhibitors regarding their ability to
preserve pancreatic islet-cell function.
In recent years, the goal of the treatment of T2DM has been shifted from merely
reducing HbA1c levels alone, to simultaneously addressing several aspects of the more
complex pathophysiologic interplay characterising T2DM, e.g. gluco- and lipotoxicity,
reduced muscle glucose uptake, hepatic insulin resistance, decreased incretin effect, increased
glucagon secretion and decreased insulin secretion, as well as improving cardiovascular risk
factors including weight, blood pressure and lipid profile [88]. Given this complexity and the
heterogeneous phenotype of patients with T2DM, it seems obvious that, in order to achieve
12
13. these aims, combination of different blood-glucose lowering agents with complementary
mechanisms of action is necessary. Indeed, in addition to addressing the multiple
pathophysiological defects of T2DM, combining agents in the early phase of the disease, may
result in early robust HbA1c lowering, thus minimize the deleterious effect of glucose
toxicity, improve residual beta-cell function and allow to use lower doses of individual agents
in order to reduce side effects [89,90]. Also, initial combination therapy, as opposed to the
step-wise approach advocated in the current guidelines [91] may prevent clinical inertia which
results in significant delays in therapeutic adjustments at the cost of accumulation of
considerable glycaemic burden and late complications [89,92]. Combination therapy that
improves both insulin secretion and peripheral or hepatic insulin sensitivity may be most
effective in preventing the natural decline in glycaemic control. However, in clinical practice,
the use of currently established anti-hyperglycaemic drugs is associated with potential side
effects that may off-set the efficacy, e.g. by adversely affecting cardiovascular risk factors
and/or hamper patient compliance. For example, SU agents lower blood glucose but do not
slow down beta-cell function deterioration [87]. Additionally, SU cause body weight gain and
hypoglycaemia, both of which are associated with increased cardiovascular risk in patients
with T2DM [93], metformin use is associated with gastro-intestinal side-effects and TZDs
cause weight gain and fluid retention, which can progress to peripheral oedema and/or overt
heart failure [91]. Therefore, new drugs such as DPP-4 inhibitors may be of great additive
value, as they not only address multiple pathophysiologic mechanisms underlying T2DM but,
to date, also seem to have a relatively favourable side-effect profile (see below). In this
regard, combining DPP-4 inhibitors with currently employed strategies that improve insulin
sensitivity, i.e. TZD and/or metformin, might be particularly suited. Interestingly, metformin
potentially increases GLP-1 levels and acts as GLP-1 sensitizer [94], resulting in a synergistic
effect when used in combination with the DPP-4 inhibitor sitagliptin as observed in healthy
humans [95]. Indeed, a recent meta-analysis shows that combination therapies are more
efficacious in improving glycaemic control than administering each of the individual drugs
alone [96]. Furthermore, the use of DPP-4 inhibitors alongside insulin replacement therapy
has been reported to be safe. The first trials that assessed the use of DPP-4 inhibitors
compared to placebo in combination with insulin treatment showed better glycaemic control
and less use of insulin despite fewer hypoglycaemic events [97,98].
Concerning implementation of incretin-based therapies, at present, the moment of
initiation in the treatment of T2DM is under debate. Current diabetes treatment-guidelines
recommend a stepwise approach, which by some authors has been termed a “treat-to-failure”
13
14. approach [99]. Accordingly, a next agent should be added whenever HbA1c rises above a
preset target level [91]. In clinical practice, however, the next therapeutic step is often taken
to late, leading to accumulation of considerable glycaemic burden [92]. In order to achieve
greater efficacy, a more aggressive approach in the early phase of T2DM has been advocated:
initiating a combination of two or more anti-hyperglycaemic agents that collectively address
multiple pathophysiological mechanisms, in order to minimize glycaemic burden over time
[89]. Furthermore, it was demonstrated that early on in the development of T2DM, when
HbA1c is just above the target of 7.0% (53 mmol/mol), postprandial hyperglycaemia mainly
contributes to the progression of the disease [100]. Taking together the findings that DPP-4
inhibition 1) improves postprandial glucose disposal; 2) already exerts a glucose lowering
effect when administered to subjects with IFG and/or IGT [72,73]; 3) does not cause
hypoglycaemia and 4) seems to preserve beta-cell function at least for the first two years of
treatment, one may conclude that early combination therapy consisting of a DPP-4 inhibitor in
addition to a drug with complementary modes of action (e.g. metformin and/or TZD) may be
needed to halt the progressive nature of T2DM.
As stated above, an advantage of DPP-4 inhibition compared to other glucose-
lowering agents, is the fact that DPP-4 inhibitors show generally mild side effects in clinical
use. Importantly, due to the glucose-dependent effect on insulin secretion, hypoglycaemia is
seldom seen during DPP-4 inhibitor monotherapy or when a DPP-4 inhibitor is added to
ongoing metformin therapy [101]. Pooled analyses from clinical trials up to two years, in
which adverse events during sitagliptin and vildagliptin therapy were evaluated, showed no
difference in incidence of adverse events, e.g. hypoglycaemic events, infection rate, skin
reaction, hepatic injury or increased risk of major cardiovascular events, compared to placebo
[102,103]. However, early clinical trials showed a higher incidence rate of infections, mainly
from the upper respiratory tract and urinary tract [104]. Moreover, recent concerns are raised
about incretin-based therapies and incidence of pancreatitis, however incidence of pancreatitis
during sitagliptin treatment was similar to that in placebo [105,106]. Due to the relative short-
term studies conducted with DPP-4 inhibitors and the recent introduction of this group in the
market, side effects need to be monitored carefully in ongoing trials and postmarketing
analysis. Furthermore, the different compounds are of diverse chemical structure and may
therefore theoretically exert different clinical efficacy and side effect profiles [107]. Thus an
aspect that should be monitored closely, is that, besides their role in glucose metabolism,
DPP-4 inhibitors might intervene with other (unknown) metabolic or immunologic pathways,
given the ubiquitous expression of DPP-4 in the human body. Up to now most and longest
14
15. trials are performed with vildagliptin and sitagliptin. Careful long-term surveillance of all
compounds from this new class of glucose-lowering agents is needed and this can be
effectuated as, according to the FDA and EMA guidance [108], all pharmaceutical companies
with DPP-4 inhibiting agents on the market or about to be launched, have committed
themselves to perform large-sized long-term outcome trials to assess long-term efficacy but in
particular cardiovascular and overall safety of the drugs (TECOS-trial for sitagliptin
NCT00790205; EXAMINE trial for alogliptin NCT 00968708; SAVOR-TIMI 53 trial for
saxagliptin NCT01107886; CAROLINA trial for linagliptin NCT01243424).
A limitation to the clinical use of DPP-4 inhibitors might be the higher cost, compared
to more established compounds such as metformin, SU and insulin. One study assessed the
cost-effectiveness of the DPP-4 inhibitor sitagliptin against the TZD rosiglitazone or SU
derivatives as add-on to metformin treatment, in which equal cost-effectiveness was
concluded [109]. However, when performing cost-effectiveness analyses in the context of
novel drugs for chronic use, it is important that not only direct but also indirect costs are
included, such as those inferred by hospital admission because of hypoglycaemia, costs
related to non-compliance due to a drug’s unfavourable side-effect profile, costs related to
drug-related body weight gain or indirect costs due to sick-leave and loss of work force
related to the disease and/or therapy, therefore more extensive cost-effectiveness analyses
should be conducted for DPP-4 inhibitor therapy.
To conclude, overall, present evidence suggests that DPP-4 inhibitors improve
pancreatic islet cell function in humans based on both static and dynamic parameters as
shown in clinical trials up to two years. However, little data indicate sustained improvements
after drug wash-out, giving doubt to the hypothesis generated in pre-clinical studies that these
agents may durably preserve beta-cell function in humans. Moreover, it is uncertain whether
DPP-4 inhibitor monotherapy may alter the progressive course of the disease by preserving
functional beta-cell mass, in the presence of persistent damaging factors such as
(gluco)lipotoxicity, and the associated oxidative stress and low grade inflammation, or
hepatic insulin resistance. As stated above, DDP-4 inhibitors may be particularly useful in the
early phase when combined with agents addressing complementary pathophysiological
mechanisms. However, long-term trials should be awaited for to assess whether treatment
with DPP-4 inhibitors durably (and equally) improves islet-cell function and whether it may
change the progressive course of T2DM by preserving beta-cell function.
15
16. List of abbreviations
AUC Area under the curve
BID Twice daily
DPP-4 Dipeptidyl peptidase-4
EMA European Medicines Agency
FDA Food and Drug Administration
GIP Glucose-dependent insulinotropic polypeptide
GLP-1 Glucagon-like peptide 1
IFG Impaired fasting glucose
IGT Impaired glucose tolerance
HbA1c Haemoglobin A1c
HOMA-B Homeostatic model assessment beta-cell function index
IVGTT Intravenous glucose tolerance test
PI/I ratio Pro-insulin to insulin ratio
QD Once daily
RCT Randomised clinical trial
SU Sulfonylurea drugs
T2DM Type 2 diabetes mellitus
TZD Thiazolidinedione
16
17. Table 1. DPP-4 inhibitors and islet cell function and morphology: preclinical studies
Effect of DPP-4 inhibition
Ref Year Animal model Intervention Islet-cell function Islet morphology
21 2002 HFD-induced diabetic 8 wk NVP DPP728 (0.12 μmol/g/day), In vivo: Improved oral glucose disposal Increased GLUT-2 expression
C57BL/6J mice orally Ex vivo: Increased pancreatic insulin secretion Preserved islet size
No difference β-cell/α-cell distribution pattern
22 2002 VDF Zucker rats 12 wk P32/98 (20 mg/kg/day), orally In vivo: Increased early phase insulin n/a
Improved hepatic and peripheral insulin sensitivity
23 2002 VDF Zucker rats 3 months P32/98 (20 mg/kg/day), orally In vivo: Improved oral glucose disposal No difference in β-cell area or islet size
Increased insulin sensitivity
Ex vivo: Increased pancreatic insulin secretion
24 2003 STZ-induced diabetic 7 wk P32/98 (20 mg/kg/day), orally In vivo: Improved oral glucose disposal Increased pancreatic insulin content
Wistar rats Increased insulin levels Increased number of β-cells
Ex vivo: Increased pancreatic insulin secretion
25 2006 HFD- and/or STZ-induced 2-3 months des-fluoro-sitagliptin In vivo: Improved oral glucose disposal Restored β-cell mass & number
diabetic mice (43, 208 and 576 mg/kg/day) or Decreased glucagon secretion. Restored β-cell/α-cell distribution pattern
glipizide (20 mg/kg/day), orally Ex vivo: Increased pancreatic insulin secretion Increased pancreatic insulin content
→ No such effect of glipizide
26 2007 DIRKO & wild type mice 8 wk vildagliptin (1 μmol/ml drinking In vivo: Improved oral glucose disposal in wild type mice n/a
on HFD water ad libitum), orally → No such effect in DIRKO-mice
27 2007 Mice with beta-cell 8-9 wk vildagliptin (3μmol/day), orally In vivo: Improved iv glucose tolerance and insulin response Restored pancreatic insulin content
hIAPP-overexpression Improved insulin response to gastric glucose Restored β-cell/α-cell distribution pattern
Ex vivo: Increased pancreatic insulin secretion
28 2008 Fatty Zucker rats with 3-8 wk P32/98 (21.61 mg/kg/day), orally In vivo: Restored non-fasting glucose levels No effect on islet size or β-cell density
impaired glucose Slighty increased glucose responsiveness of the
tolerance β-cell
29 2008 Diabetic C57BL/KSJ 8 wk vildagliptin (1mg/kg/day) In vivo: Improved glucose tolerance Increased pancreatic β-cell area
db/db mice and/or valsartan (10mg/kg/day), orally Increased β-cell proliferation
Reduced apoptosis
→ Greater effect in combination with valsartan
30 2008 STZ-induced diabetic Islet transplantation plus 4 wk sitagliptin In vivo: Improved glucose disposal Sustained islet graft preservation (measured by
mice (added to ad libitum diet), orally Increased insulin levels Positron Emission Tomography [PET] imaging)
Decreased glucagon levels
31 2009 Diabetic Lepob/Lepob mice 4-5 wk alogliptin (45.7 mg/kg/day) In vivo: Improved HbA1c, fasting & non-fasting glucose Increased pancreatic insulin content
and/or pioglitazon (4.0 mg/kg/day), orally Increased insulin levels → Greater effect in combination with
Decreased glucagon levels pioglitazon
32 2009 HFD- and STZ-induced 10 wk sitagliptin (280 mg/kg/day) In vivo: Improved oral glucose disposal Restored β-cell/α-cell distribution pattern
diabetic mice or glipizide (20 mg/kg/day), orally Ex vivo: Increased pancreatic insulin secretion Restored pancreatic insulin content
No effect on proliferation
→ No such effect of glipizide
33 2010 C57BI/6J mice on HFD 12 wk des-fluoro-sitagliptin (4 g/kg), In vivo: Improved oral glucose disposal No difference in islet number and area
orally Increased insulin levels Improved percentage of small islets
Ex vivo: Increased pancreatic insulin secretion Reduced inflammatory cytokine expression
34 2010 Prediabetic db/db mice 4 wk alogliptin (72.8 mg/kg/day) and/or In vivo: Improved fasting glucose and HbA1c Increased pancreatic insulin content
voglibose (1.8 mg/kg/day), orally Increased insulin levels; decreased glucagon levels Increased GLUT-2 and PDX1 expression
→ Greater effect in combination with voglibose → Greater effect in combination with voglibose
No difference in pancreatic glucagon content
35 2011 Neonatal Wistar rats 19 days vildagliptin (60 mg/kg/day), In vivo: Small increase in insulin levels Enhanced β-cell replication
orally No effect on non-fasting glucose Reduced apoptosis
→ Durable effects after 12-days drug washout
Ref: reference; VDF: Vancouver diabetic fatty; STZ: streptozotocin; HFD: high fat diet; DIRKO: dual incretin-
receptor knock-out; hIAPP: human islet amyloid polypeptide; P32/98: isoleucine thiazolidide.
17
21. Table 5. DPP-4 inhibitors and dynamic, postprandial, measures of islet cell function: clinical studies,
combination therapy
Δ IGI (%) Δ AUCinsulin/AUCglucose (%) Δ AUCGlucagon (%)
vs vs vs
Ref Year Intervention (N) Duration vs BL P P vs BL P P vs BL P P
COM COM COM
Sitagliptin as add-on to metformin
52 2006 sitagliptin 100 mg QD (453) 24 wk +23.5 n/a +28.8 <0.001
placebo (224) -5.3
53 2007 sita/met 100mg/1000mg (183) 24 wk +50.0 n/a +50.0 <0.001
sita/met 100mg/2000mg (180) +50.0 +50.0 <0.001
metformin 1000mg (179) +25.0 +25.0 <0.001
metformin 2000mg (179) +27.8 +27.8 <0.05
sitagliptin 100mg (178) +36.7 +36.7 <0.05
placebo (169) 0
77 2008 sitagliptin 100 mg QD (95) 2 wk n/a n/a -49‡ 0.02 n/a 0.0017 n/a n/a n/a 0.0011 n/a 0.0011
exenatide 10 μgr BID (95) crossover n/a n/a † † † †
54§ 2010 sitagliptin 100 mg QD (10) 48 wk n/a n/a n/a 0.23 -16.1 n/a +15.6 0.23
placebo (11) -31.7 n/a
57 2010 sitagliptin 100 mg QD (248) 2 year +15.8 n/a +40.2‡ n/a +8.9 n/a +3.0‡ n/a
glipizide 20 mg QD (256) -24.4 +5.9 n/a
Sitagliptin as add-on to metformin and/or
sulfonylurea
61 2007 sitagliptin 100 mg QD (222) 24 wk +14.5 <0,05 +25.8 <0.05
placebo (219) -11.3
Vildagliptin as add-on to metformin
75 2005 vildagliptin 50 mg QD (31) 52 wk +72.3 sign +96.8 sign
placebo (26) -24.5 sign
76 2007 vildagliptin 50 mg QD (177) 24 wk n/a n/a n/a <0.001
vildagliptin 100 mg QD (185) <0.001
placebo (182)
<0.001
78 2010 vildagliptin 50 mg BID 2 year n/a n/a n/a
‡
glimepiride 6 mg QD
Saxagliptin as add-on to metformin
60** 2009 saxagliptin 2.5 mg QD (192) 24 wk n/a ns n/a ns
saxagliptin 5 mg QD (191) n/a ns n/a ns
saxagliptin 10 mg QD (181) n/a ns n/a ns
placebo (179) n/a ns
Vildagliptin as add-on to sulfonylurea
62 2008 vildagliptin 50 mg QD (170) 24 wk +16.6 n/a +22.7 0.024
vildagliptin 50 mg BID (169) +17.5 +23.6 0.014
placebo (176) -6.1
Sitagliptin as add-on to thiazolidinedione
64 2011 sitagliptin 100 mg QD (217) 24 wk +50.0 sign +50.0 <0.001 n/a
placebo (208) 0 ns
Vildagliptin as add-on to thiazolidinedione
79 2007 vildagliptin 100 mg QD (48) 24 wk +37.0 n/a +27.0 <0.01
vildagliptin 50 mg QD (48) +35.0 +25.0 <0.01
placebo (42) +10.0
80 2007 vildagliptin 100 mg QD (154) 24 wk n/a n/a n/a n/a
pioglitazon 30 mg QD (161)
vilda+pio 50/15 mg QD (144) <0.05*
vilda+pio 100/30 mg QD (148)
Saxagliptin as add-on to thiazolidinedione
65** 2009 saxagliptin 2.5 mg QD (195) 24 wk +91.7 n/a +156.7 Sign -4.1 n/a -1.9 0.5482
saxagliptin 5 mg QD (186) +78.6 n/a +143.6 sign -8.1 -5.9 0.0722
placebo (184) -65 n/a -2.2
Percentage change as reported in the cited reference or calculated from reported figures if possible. Measures are
derived from mixed meal tolerance tests, unless otherwise stated. Ref: reference; IGI: insulinogenic index; AUC:
area under the curve; pio: pioglitazone; vs BL: versus baseline; vs COM: versus comparator (placebo unless
otherwise stated); sign: significant, level of significance not reported in reference; ns: non-significant; n/a: not
available. * P-value for between treatment difference vs. pioglitazone; † P-value for between treatment
difference vs. sitagliptin; ** use of oral glucose tolerance test in stead of mixed meal test § IGI and
AUCinsulin/AUCglucose are corrected for insulin resistance; ‡active comparator.
21
22. Table 6. Clinical effect of DPP-4 inhibitors on pancreatic beta-cell function
Effect of clinical use of DPP-4 inhibitors on pancreatic beta-cell function
Static Dynamic Sustainability
DPP-4 Hyperglycaemic Effect after 1 Effect after ≥
inhibitor HOMA-B PI/I ratio IGI AUCinsulin/glucose Modelling IVGTT Clamp year treatment 4 wk washout
Sitagliptin ↑ ↑ ↑/= ↑/= ↑/= n/a ↑ ↑ =
Vildagliptin ↑ ↑/= ↑/= ↑/= ↑/= ↑ ↑ ↑ =
Saxagliptin ↑ n/a ↑/= n/a n/a n/a n/a n/a n/a
Alogliptin = ↑ n/a n/a n/a n/a n/a n/a n/a
Linagliptin ↑ ↑ n/a = n/a n/a n/a n/a n/a
IGI: insulinogenic index; AUC: area under the curve; HOMA-B: homeostatic model assessment beta-cell
function index; PI/I ratio: pro-insulin-to-insulin ratio; IVGTT: intravenous glucose-tolerance test; ↑: beneficial
effects of DPP-4 inhibitor treatment in all studies; ↑/=: beneficial effects of DPP-4 inhibitor treatment in some
studies, but not all; =: no effect of DPP-4 inhibitor treatment; n/a: data not available.
22
23. Reference List
1. Wild S., Roglic G., Green A., Sicree R., King H. Global prevalence of diabetes:
estimates for the year 2000 and projections for 2030. Diabetes Care 2004; 27:1047-
1053.
2. Weyer C., Bogardus C., Mott D.M., Pratley R.E. The natural history of insulin
secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes
mellitus. J Clin Invest 1999; 104:787-794.
3. Turner R.C., Cull C.A., Stratton I.M. et al. UK Prospective Diabetes Study 16 -
Overview of 6 Years Therapy of Type-II Diabetes - A Progressive Disease. Diabetes
1995; 44:1249-1258.
4. Matveyenko A.V., Butler P.C. Relationship between beta-cell mass and diabetes
onset. Diabetes Obes Metab 2008; 10 Suppl 4:23-31.
5. Shah P., Vella A., Basu A., Basu R., Schwenk W.F., Rizza R.A. Lack of suppression
of glucagon contributes to postprandial hyperglycemia in subjects with type 2 diabetes
mellitus. J Clin Endocrinol Metab 2000; 85:4053-4059.
6. Heine R.J., Diamant M., Mbanya J.C., Nathan D.M. Management of hyperglycaemia
in type 2 diabetes. British Medical Journal 2006; 333:1200-1204A.
7. Nauck M., Stockmann F., Ebert R., Creutzfeldt W. Reduced Incretin Effect in Type-2
(Non-Insulin-Dependent) Diabetes. Diabetologia 1986; 29:46-52.
8. Salehi M., Aulinger B.A., D'Alessio D.A. Targeting beta-cell mass in type 2 diabetes:
promise and limitations of new drugs based on incretins. Endocr Rev 2008; 29:367-
379.
9. Burcelin R., Da C.A., Drucker D., Thorens B. Glucose competence of the hepatoportal
vein sensor requires the presence of an activated glucagon-like peptide-1 receptor.
Diabetes 2001; 50:1720-1728.
10. Balkan B., Li X. Portal GLP-1 administration in rats augments the insulin response to
glucose via neuronal mechanisms. Am J Physiol Regul Integr Comp Physiol 2000;
279:R1449-R1454.
11. Holst J.J., Deacon C.F. Glucagon-like peptide-1 mediates the therapeutic actions of
DPP-IV inhibitors. Diabetologia 2005; 48:612-615.
12. Asmar M., Bache M., Knop F.K., Madsbad S., Holst J.J. Do the actions of glucagon-
like peptide-1 on gastric emptying, appetite, and food intake involve release of amylin
in humans? J Clin Endocrinol Metab 2010; 95:2367-2375.
13. Kielgast U., Asmar M., Madsbad S., Holst J.J. Effect of glucagon-like peptide-1 on
alpha- and beta-cell function in C-peptide-negative type 1 diabetic patients. J Clin
Endocrinol Metab 2010; 95:2492-2496.
14. Meier J.J., Gallwitz B., Siepmann N. et al. Gastric inhibitory polypeptide (GIP) dose-
23
24. dependently stimulates glucagon secretion in healthy human subjects at euglycaemia.
Diabetologia 2003; 46:798-801.
15. Hansotia T., Drucker D.J. GIP and GLP-1 as incretin hormones: lessons from single
and double incretin receptor knockout mice. Regul Pept 2005; 128:125-134.
16. Baggio L.L., Drucker D.J. Biology of incretins: GLP-1 and GIP. Gastroenterology
2007; 132:2131-2157.
17. Ahren B., Landin-Olsson M., Jansson P.A., Svensson M., Holmes D., Schweizer A.
Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and
reduces glucagon levels in type 2 diabetes. J Clin Endocrinol Metab 2004; 89:2078-
2084.
18. Mentlein R. Dipeptidyl-peptidase IV (CD26)--role in the inactivation of regulatory
peptides. Regul Pept 1999; 85:9-24.
19. Ahren B., Hughes T.E. Inhibition of dipeptidyl peptidase-4 augments insulin secretion
in response to exogenously administered glucagon-like peptide-1, glucose-dependent
insulinotropic polypeptide, pituitary adenylate cyclase-activating polypeptide, and
gastrin-releasing peptide in mice. Endocrinology 2005; 146:2055-2059.
20. Fakhoury W.K., Lereun C., Wright D. A meta-analysis of placebo-controlled clinical
trials assessing the efficacy and safety of incretin-based medications in patients with
type 2 diabetes. Pharmacology 2010; 86:44-57.
21. Reimer M.K., Holst J.J., Ahren B. Long-term inhibition of dipeptidyl peptidase IV
improves glucose tolerance and preserves islet function in mice. Eur J Endocrinol
2002; 146:717-727.
22. Pospisilik J.A., Stafford S.G., Demuth H.U., McIntosh C.H., Pederson R.A. Long-
term treatment with dipeptidyl peptidase IV inhibitor improves hepatic and peripheral
insulin sensitivity in the VDF Zucker rat: a euglycemic-hyperinsulinemic clamp study.
Diabetes 2002; 51:2677-2683.
23. Pospisilik J.A., Stafford S.G., Demuth H.U. et al. Long-term treatment with the
dipeptidyl peptidase IV inhibitor P32/98 causes sustained improvements in glucose
tolerance, insulin sensitivity, hyperinsulinemia, and beta-cell glucose responsiveness
in VDF (fa/fa) Zucker rats. Diabetes 2002; 51:943-950.
24. Pospisilik J.A., 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; 52:741-750.
25. Mu J., Woods J., Zhou Y.P. 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; 55:1695-1704.
26. Flock G., Baggio L.L., Longuet C., Drucker D.J. Incretin receptors for glucagon-like
peptide 1 and glucose-dependent insulinotropic polypeptide are essential for the
sustained metabolic actions of vildagliptin in mice. Diabetes 2007; 56:3006-3013.
24
25. 27. Ahren B., Winzell M.S., Wierup N., Sundler F., Burkey B., Hughes T.E. DPP-4
inhibition improves glucose tolerance and increases insulin and GLP-1 responses to
gastric glucose in association with normalized islet topography in mice with beta-cell-
specific overexpression of human islet amyloid polypeptide. Regul Pept 2007; 143:97-
103.
28. Augstein P., Berg S., Heinke P. et al. Efficacy of the dipeptidyl peptidase IV inhibitor
isoleucine thiazolidide (P32/98) in fatty Zucker rats with incipient and manifest
impaired glucose tolerance. Diabetes Obes Metab 2008; 10:850-861.
29. Cheng Q., Law P.K., de G.M., Leung P.S. Combination of the dipeptidyl peptidase IV
inhibitor LAF237 [(S)-1-[(3-hydroxy-1-adamantyl)ammo]acetyl-2-cyanopyrrolidine]
with the angiotensin II type 1 receptor antagonist valsartan [N-(1-oxopentyl)-N-[[2'-
(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl]methyl]-L- valine] enhances pancreatic islet
morphology and function in a mouse model of type 2 diabetes. J Pharmacol Exp Ther
2008; 327:683-691.
30. Kim S.J., Nian C., Doudet D.J., McIntosh C.H. Inhibition of dipeptidyl peptidase IV
with sitagliptin (MK0431) prolongs islet graft survival in streptozotocin-induced
diabetic mice. Diabetes 2008; 57:1331-1339.
31. Moritoh Y., Takeuchi K., Asakawa T., Kataoka O., Odaka H. The dipeptidyl
peptidase-4 inhibitor alogliptin in combination with pioglitazone improves glycemic
control, lipid profiles, and increases pancreatic insulin content in ob/ob mice. Eur J
Pharmacol 2009; 602:448-454.
32. Mu J., Petrov A., Eiermann G.J. et al. Inhibition of DPP-4 with sitagliptin improves
glycemic control and restores islet cell mass and function in a rodent model of type 2
diabetes. Eur J Pharmacol 2009; 623:148-154.
33. Dobrian A.D., Ma Q., Lindsay J.W. et al. Dipeptidyl peptidase-4 inhibitor sitagliptin
reduces local inflammation in adipose tissue and in pancreatic islets of obese mice. Am
J Physiol Endocrinol Metab 2010.
34. Moritoh Y., Takeuchi K., Hazama M. Combination treatment with alogliptin and
voglibose increases active GLP-1 circulation, prevents the development of diabetes
and preserves pancreatic beta-cells in prediabetic db/db mice. Diabetes Obes Metab
2010; 12:224-233.
35. Duttaroy A., Voelker F., Merriam K. et al. The DPP-4 inhibitor vildagliptin increases
pancreatic beta cell mass in neonatal rats. Eur J Pharmacol 2011; 650:703-707.
36. Matthews D.R., Hosker J.P., Rudenski A.S., Naylor B.A., Treacher D.F., Turner R.C.
Homeostasis model assessment: insulin resistance and beta-cell function from fasting
plasma glucose and insulin concentrations in man. Diabetologia 1985; 28:412-419.
37. Ward W.K., LaCava E.C., Paquette T.L., Beard J.C., Wallum B.J., Porte D., Jr.
Disproportionate elevation of immunoreactive proinsulin in type 2 (non-insulin-
dependent) diabetes mellitus and in experimental insulin resistance. Diabetologia
1987; 30:698-702.
38. Mari A., Tura A., Gastaldelli A., Ferrannini E. Assessing insulin secretion by
25
26. modeling in multiple-meal tests - Role of potentiation. Diabetes 2002; 51:S221-S226.
39. Breda E., Cavaghan M.K., Toffolo G., Polonsky K.S., Cobelli C. Oral glucose
tolerance test minimal model indexes of beta-cell function and insulin sensitivity.
Diabetes 2001; 50:150-158.
40. Aschner P., Kipnes M.S., Lunceford J.K., Sanchez M., Mickel C., Williams-Herman
D.E. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on
glycemic control in patients with type 2 diabetes. Diabetes Care 2006; 29:2632-2637.
41. Raz I., Hanefeld M., Xu L., Caria C., Williams-Herman D., Khatami H. Efficacy and
safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients
with type 2 diabetes mellitus. Diabetologia 2006; 49:2564-2571.
42. Hanefeld M., Herman G.A., Wu M., Mickel C., Sanchez M., Stein P.P. Once-daily
sitagliptin, a dipeptidyl peptidase-4 inhibitor, for the treatment of patients with type 2
diabetes. Curr Med Res Opin 2007; 23:1329-1339.
43. Scott R., Wu M., Sanchez M., Stein P. Efficacy and tolerability of the dipeptidyl
peptidase-4 inhibitor sitagliptin as monotherapy over 12 weeks in patients with type 2
diabetes. Int J Clin Pract 2007; 61:171-180.
44. Nonaka K., Kakikawa T., Sato A. et al. Efficacy and safety of sitagliptin monotherapy
in Japanese patients with type 2 diabetes. Diabetes Res Clin Pract 2008; 79:291-298.
45. 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. Diabetes Obes Metab 2005; 7:692-698.
46. Pratley R.E., Schweizer A., Rosenstock J. et al. Robust improvements in fasting and
prandial measures of beta-cell function with vildagliptin in drug-naive patients:
analysis of pooled vildagliptin monotherapy database. Diabetes Obes Metab 2008;
10:931-938.
47. DeFronzo R.A., Fleck P.R., Wilson C.A., Mekki Q. Efficacy and safety of the
dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes and
inadequate glycemic control: a randomized, double-blind, placebo-controlled study.
Diabetes Care 2008; 31:2315-2317.
48. Rosenstock J., Sankoh S., List J.F. Glucose-lowering activity of the dipeptidyl
peptidase-4 inhibitor saxagliptin in drug-naive patients with type 2 diabetes. Diabetes
Obes Metab 2008; 10:376-386.
49. Rosenstock J., guilar-Salinas C., Klein E., Nepal S., List J., Chen R. Effect of
saxagliptin monotherapy in treatment-naive patients with type 2 diabetes. Curr Med
Res Opin 2009; 25:2401-2411.
50. Del Prato S., Barnett A.H., Huisman H., Neubacher D., Woerle H.J., Dugi K.A. Effect
of linagliptin monotherapy on glycaemic control and markers of beta-cell function in
patients with inadequately controlled type 2 diabetes: a randomised controlled trial.
Diabetes Obes Metab 2010.
26
27. 51. Charbonnel B., Karasik A., Liu J., Wu M., Meininger G. Efficacy and safety of the
dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in
patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes
Care 2006; 29:2638-2643.
52. Goldstein B.J., Feinglos M.N., Lunceford J.K., Johnson J., Williams-Herman D.E.
Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4
inhibitor, and metformin on glycemic control in patients with type 2 diabetes.
Diabetes Care 2007; 30:1979-1987.
53. Retnakaran R., Qi Y., Opsteen C., Vivero E., Zinman B. Initial short-term intensive
insulin therapy as a strategy for evaluating the preservation of beta-cell function with
oral antidiabetic medications: a pilot study with sitagliptin. Diabetes Obes Metab
2010; 12:909-915.
54. Nauck M.A., Meininger G., Sheng D., Terranella L., Stein P.P. Efficacy and safety of
the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea,
glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone:
a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab 2007; 9:194-
205.
55. Scott R., Loeys T., Davies M.J., Engel S.S. Efficacy and safety of sitagliptin when
added to ongoing metformin therapy in patients with type 2 diabetes. Diabetes Obes
Metab 2008; 10:959-969.
56. Seck T., Nauck M., Sheng D. et al. Safety and efficacy of treatment with sitagliptin or
glipizide in patients with type 2 diabetes inadequately controlled on metformin: a 2-
year study. Int J Clin Pract 2010; 64:562-576.
57. Ahren B., Pacini G., Tura A., Foley J.E., Schweizer A. Improved meal-related insulin
processing contributes to the enhancement of B-cell function by the DPP-4 inhibitor
vildagliptin in patients with type 2 diabetes. Horm Metab Res 2007; 39:826-829.
58. Nauck M.A., Ellis G.C., Fleck P.R., Wilson C.A., Mekki Q. Efficacy and safety of
adding the dipeptidyl peptidase-4 inhibitor alogliptin to metformin therapy in patients
with type 2 diabetes inadequately controlled with metformin monotherapy: a
multicentre, randomised, double-blind, placebo-controlled study. Int J Clin Pract
2009; 63:46-55.
59. DeFronzo R.A., Hissa M.N., Garber A.J. et al. The efficacy and safety of saxagliptin
when added to metformin therapy in patients with inadequately controlled type 2
diabetes with metformin alone. Diabetes Care 2009; 32:1649-1655.
60. Hermansen K., Kipnes M., Luo E., Fanurik D., Khatami H., Stein P. Efficacy and
safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2
diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and
metformin. Diabetes Obes Metab 2007; 9:733-745.
61. Garber A.J., Foley J.E., Banerji M.A. et al. Effects of vildagliptin on glucose control
in patients with type 2 diabetes inadequately controlled with a sulphonylurea. Diabetes
Obes Metab 2008; 10:1047-1056.
27
28. 62. Rosenstock J., Brazg R., Andryuk P.J., Lu K., Stein P. Efficacy and safety of the
dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in
patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind,
placebo-controlled, parallel-group study. Clin Ther 2006; 28:1556-1568.
63. Yoon K.H., Shockey G.R., Teng R. et al. Effect of initial combination therapy with
sitagliptin, a dipeptidyl peptidase-4 inhibitor, and pioglitazone on glycemic control
and measures of beta-cell function in patients with type 2 diabetes. Int J Clin Pract
2011; 65:154-164.
64. Hollander P., Li J., Allen E., Chen R. Saxagliptin added to a thiazolidinedione
improves glycemic control in patients with type 2 diabetes and inadequate control on
thiazolidinedione alone. J Clin Endocrinol Metab 2009; 94:4810-4819.
65. Herman G.A., Bergman A., Stevens C. et al. Effect of single oral doses of sitagliptin, a
dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral
glucose tolerance test in patients with type 2 diabetes. Journal of Clinical
Endocrinology and Metabolism 2006; 91:4612-4619.
66. Mari A., Scherbaum W.A., Nilsson P.M. et al. Characterization of the influence of
vildagliptin on model-assessed beta-cell function in patients with type 2 diabetes and
mild hyperglycemia. Journal of Clinical Endocrinology & Metabolism 2008; 93:103-
109.
67. Scherbaum W.A., Schweizer A., Mari A. et al. Efficacy and tolerability of vildagliptin
in drug-naive patients with type 2 diabetes and mild hyperglycaemia*. Diabetes Obes
Metab 2008; 10:675-682.
68. Scherbaum W.A., Schweizer A., Mari A. et al. Evidence that vildagliptin attenuates
deterioration of glycaemic control during 2-year treatment of patients with type 2
diabetes and mild hyperglycaemia. Diabetes Obes Metab 2008; 10:1114-1124.
69. Azuma K., Radikova Z., Mancino J. et al. Measurements of islet function and glucose
metabolism with the dipeptidyl peptidase 4 inhibitor vildagliptin in patients with type
2 diabetes. Journal of Clinical Endocrinology & Metabolism 2008; 93:459-464.
70. Ahren B., Schweizer A., Dejager S. et al. Vildagliptin enhances islet responsiveness to
both hyper- and hypoglycemia in patients with type 2 diabetes. J Clin Endocrinol
Metab 2009; 94:1236-1243.
71. Dalla Man C., Bock G., Giesler P.D. et al. Dipeptidyl peptidase-4 inhibition by
vildagliptin and the effect on insulin secretion and action in response to meal ingestion
in type 2 diabetes. Diabetes Care 2009; 32:14-18.
72. Utzschneider K.M., Tong J., Montgomery B. et al. The dipeptidyl peptidase-4
inhibitor vildagliptin improves beta-cell function and insulin sensitivity in subjects
with impaired fasting glucose. Diabetes Care 2008; 31:108-113.
73. Rosenstock J., Holst J.J., Foley J.E. et al. Effects of the dipeptidyl peptidase-IV
inhibitor vildagliptin on incretin hormones, islet function, and postprandial glycemia
in subjects with impaired glucose tolerance. Diabetes Care 2008; 31:30-35.
28