Type 2 diabetes mellitus is a complex and progressive disease that is showing an apparently unstoppable increase worldwide. Although there is general agreement on the first-line use of metformin in most patients with type 2 diabetes, the ideal drug sequence after metformin failure is an area of increasing uncertainty. New treatment strategies target pancreatic islet dysfunction, in particular gut-derived incretin hormones. Inhibition of the enzyme dipeptidyl peptidase-4 (DPP-4) slows degradation of endogenous glucagon-like peptide-1 (GLP-1) and thereby enhances and prolongs the action of the endogenous incretin hormones. The five available DPP-4 inhibitors, also known as ‘gliptins’ (sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin), are small molecules used orally with similar overall clinical efficacy and safety profiles in patients with type 2 diabetes. The main differences between the five gliptins on the market include: potency, target selectivity, oral bioavailability, long or short half-life, high or low binding to plasma proteins, metabolism, presence of active or inactive metabolites, excretion routes, dosage adjustment for renal and liver insufficiency, and potential drug–drug interactions. On average, treatment with gliptins is expected to produce a mean glycated hemoglobin (HbA1c) decrease of 0.5%–0.8%, with about 40% of diabetic subjects at target for the HbA1c goal <7%. There are very few studies comparing DPP-4 inhibitors. Alogliptin as monotherapy or added to metformin, pioglitazone, glibenclamide, voglibose, or insulin therapy significantly improves glycemic control compared with placebo in adult or elderly patients with inadequately controlled type 2 diabetes. In the EXAMINE trial, alogliptin is being compared with placebo on cardiovascular outcomes in approximately 5,400 patients with type 2 diabetes. In clinical studies, DPP-4 inhibitors were generally safe and well tolerated. However, there are limited data on their tolerability, due to their relatively recent marketing approval. Alogliptin will be used most when avoidance of hypoglycemic events is paramount, such as in patients with congestive heart failure, renal failure, and liver disease, and in the elderly.
type 2 diabetes; DPP-4 inhibitors; alogliptin
Saxagliptin is a novel dipeptidyl peptidase-4 inhibitor (DPP-4 inhibitor) for the treatment of type 2 diabetes, with a duration profile for once daily dosing. It is highly selective for DPP-4 in comparison to other enzymes of the dipeptidyl peptidase family. DPP-4 inhibitors elevate plasma concentrations of the incretin hormones glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP). This effect results in a glucose-dependent stimulation of insulin secretion and an inhibition of glucagon secretion without an intrinsic risk for hypoglycemia. In comparison to sulfonylureas and thiazolidinediones that promote weight gain, DPP-4 inhibitors are weight neutral. Saxagliptin has been approved by the FDA for the US and by the EMEA for Europe in 2009. Clinical trials showed a dose-dependent inhibition of DPP-4 by saxagliptin in doses ranging from 2.5 to 100 mg daily without serious side effects. Type 2 diabetic patients receiving 5 mg to 10 mg saxagliptin once daily had a significant lowering of HbA1c and glycemic parameters along with good tolerability and safety. Saxagliptin has demonstrated a good efficacy for glycemic parameters in various patient populations either in monotherapy or in combination with metformin and other oral antidiabetic drugs as well as a favorable cardiovascular profile. With its high selectivity for DPP-4 and its clinical and cardiovascular profile, saxagliptin is an attractive novel DPP-4 inhibitor.
type 2 diabetes; diabetes therapy; DPP-4 inhibitors; incretin based therapy; GLP-1; saxagliptin
Saxagliptin is a selective and potent dipeptidyl peptidase (DPP)-4 inhibitor, approved as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes mellitus (T2DM) in the USA on July 2009, and had been launched globally in over 86 countries by September 2013. In patients with T2DM, once-daily administration of saxagliptin before breakfast achieves sustained inhibition of plasma DPP-4 activity and reduction of postprandial hyperglycemia, including after dinner, associated with an increase in plasma glucagon-like peptide-1 levels. This paper reviews the safety and efficacy of saxagliptin in Japanese patients with T2DM. The clinical development study in Japan supported its usefulness for the disease. Saxagliptin 1, 2.5, and 5 mg led to significant improvements in glycated hemoglobin (HbA1c), and was generally well tolerated. Treatment with saxagliptin 5 mg induced a sustained reduction in HbA1c over 52 weeks. Long-term combination therapy with saxagliptin and other oral hypoglycemic agents also provided sustained glycemic control and was well tolerated for up to 52 weeks. Saxagliptin as add-on to sulfonylureas or glinides has a tendency to increase hypoglycemia, but not with other oral antidiabetic agents, such as α-glucosidase inhibitors, metformin, or thiazolidinediones. The results of clinical trials have confirmed the long-term efficacy and safety of saxagliptin monotherapy as well as its use as add-on combination therapy, and support its usefulness as a therapeutic agent for T2DM. Saxagliptin has less concern for hypoglycemia and weight gain, which often becomes problematic in routine care of T2DM. Meta-analysis of clinical trials in the USA showed no evidence of increased risk of cardiovascular events associated with saxagliptin, suggesting the superior of saxagliptin in terms of safety. Recently, investigators in the SAVOR-TIMI (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction) 53 study suggested that DPP-4 inhibition with saxagliptin did not increase or decrease the rate of ischemic events, although the rate of hospitalization for heart failure was increased. Although saxagliptin improves glycemic control, other approaches are necessary to reduce cardiovascular risk in patients with diabetes. Saxagliptin is applicable for various pathological conditions, and is considered to be clinically significant as a new therapeutic option for Japanese patients with T2DM.
dipeptidyl peptidase-4; incretin hormones; saxagliptin; type 2 diabetes mellitus; Japan; efficacy; safety; patient acceptability
To assess the pharmacokinetics of vildagliptin at different doses and build a mechanism-based population model that simultaneously describes vildagliptin pharmacokinetics and its effects on DPP-4 activity based on underlying physiology and biology.
Vildagliptin concentrations and DPP-4 activity vs. time from 13 type 2 diabetic patients after oral vildagliptin 10, 25 or 100 mg and placebo twice daily for 28 days were co-modelled. NONMEM VI and S-ADAPT were utilized for population modelling.
A target-mediated drug disposition (TMDD) model accounting for capacity-limited high affinity binding of vildagliptin to DPP-4 in plasma and tissues had good predictive performance. Modelling the full time course of the vildagliptin-DPP-4 interaction suggested parallel vildagliptin dissociation from DPP-4 by a slow first-order process and hydrolysis by DPP-4 to an inactive metabolite as a disposition mechanism. Due to limited amounts of DPP-4, vildagliptin concentrations increased slightly more than dose proportionally. This newly proposed model and the parameter estimates are supported by published in vitro studies. Mean parameter estimates (inter-individual coefficient of variation) were: non-saturable clearance 36 l h−1 (25%), central volume of distribution 22 l (37%), half-life of dissociation from DPP-4 1.1 h (94%) and half-life of hydrolysis 6.3 h (81%).
Vildagliptin is both an inhibitor and substrate for DPP-4. By utilizing the TMDD approach, slow dissociation of vildagliptin from DPP-4 was found in patients and the half-life of hydrolysis by DPP-4 estimated. This model can be used to predict DPP-4 inhibition effects of other dosage regimens and be modified for other DPP-4 inhibitors to differentiate their properties.
DPP-4 inhibitor; mechanism-based population modelling; pharmacokinetics; type 2 diabetes mellitus; vildagliptin
Type 2 diabetes is associated with decreased incretin hormone response to an oral glucose load, and a progressive decline in postprandial glucagon-like peptide-1 (GLP-1) secretion. Incretin-based therapies offer a new option for treatment of type 2 diabetes. Saxagliptin, a potent, selective dipeptidyl peptidase-4 (DPP-4) inhibitor specifically designed for extended inhibition of the DPP-4 enzyme, causes increased endogenous GLP-1 concentration. In a phase 3 clinical trials program of 24 weeks duration, saxagliptin was studied in 6 multicenter, multinational, randomized, controlled studies and in combination with 3 of the most commonly administered oral antidiabetic drugs: metformin, glyburide and a thiozolidinedione (TZD). Saxagliptin provided significant reductions in hemoglobin HbA1c when given with metformin, glyburide, a TZD, or as monotherapy. Saxagliptin also reduced fasting plasma glucose and 2-hour post-prandial glucose in each of these studies, and was weight and lipid neutral. Saxagliptin was well tolerated and had a low risk of hypoglycemia when used as monotherapy.
saxagliptin; incretins; type 2 diabetes; DPP-4 inhibitors
Saxagliptin (Onglyza™) is a potent, selective, once-daily dipeptidyl peptidase-4 (DPP-4) inhibitor indicated for improving glycemic control in patients with type 2 diabetes (T2D). By blocking DPP-4, saxagliptin increases and prolongs the effects of incretins, a group of peptide hormones released by intestinal cells after meals, which stimulate glucose-dependent insulin secretion to lower blood glucose. In controlled clinical trials, saxagliptin administered as monotherapy or in combination with metformin, glyburide, or a thiazolidinedione improved glycemic control in a clinically significant manner, reflected by significant decreases in glycated hemoglobin (monotherapy, −0.5%; add-on to metformin, thiazolidinedione, or sulfonylurea, −0.6% to 0.9%; initial combination with metformin, −2.5%), fasting plasma glucose, and postprandial glucose compared with controls. Additionally, saxagliptin improved β-cell function, reflected as increases in homeostasis model assessment (HOMA)-2β. Saxagliptin was generally well tolerated; it did not increase hypoglycemia compared with controls, and was weight neutral. A meta-analysis of Phase II and III trials showed that saxagliptin did not increase the risk of major cardiovascular events. Professional organizations have updated their guidelines for T2D to include a DPP-4 inhibitor as an early treatment option—either as initial therapy in combination with metformin, or as add-on therapy for patients whose glycemia is inadequately controlled by a single oral antidiabetic drug.
saxagliptin; dipeptidyl peptidase-4 (DPP-4) inhibitor; type 2 diabetes
To investigate the effect of co-administration of rifampicin, a potent inducer of cytochrome P450 (CYP) 3A4 enzymes, on the pharmacokinetics (PK) and pharmacodynamics (PD) of saxagliptin and 5-hydroxy saxagliptin in healthy subjects. Saxagliptin is metabolized by CYP3A4/3A5 to 5-hydroxy saxagliptin, its major pharmacologically active metabolite.
In a non-randomized, open label, single sequence design, 14 healthy subjects received single oral doses of saxagliptin 5 mg with and without steady-state rifampicin (600 mg once daily for 6 days). PK (saxagliptin and 5-hydroxy saxagliptin) and PD (plasma DPP-4 activity) were measured for up to 24 h on days 1 and 7.
Concomitant administration with rifampicin resulted in 53% (point estimate 0.47, 90% CI 0.38, 0.57) and 76% (point estimate 0.24, 90% CI 0.21, 0.27) decreases in the geometric mean Cmax and AUC values of saxagliptin, respectively, with a 39% (point estimate 1.39, 90% CI 1.23, 1.56) increase in the geometric mean Cmax and no change (point estimate 1.03, 90% CI 0.97, 1.09) in the AUC of 5-hydroxy saxagliptin. Similar maximum % inhibition and area under the % inhibition−time effect curve over 24 h for DPP-4 activity were observed when saxagliptin was administered alone or with rifampicin. The saxagliptin total active moieties exposure (AUC) decreased by 27% (point estimate 0.73, 90% CI 0.66, 0.81). Saxagliptin with or without rifampicin in this study was generally well tolerated.
Lack of change of PD effect of saxagliptin is consistent with the observed 27% reduction in systemic exposure to the total active moieties, which is not considered clinically meaningful. Based on these findings, it is not necessary to adjust the saxagliptin dose when co-administered with rifampicin.
dipeptidyl peptidase-4 (DPP-4) inhibitor; rifampicin; rifampin; saxagliptin
The aim of this study was to evaluate the dipeptidyl peptidase-IV (DPP-IV) inhibitor sitagliptin with respect to mode of inhibition and its in vivo duration of inhibition and efficacy in type 2 diabetes animal model.
Materials and Methods:
DPP-IV enzyme assay was carried out in human plasma (10 μL) or human recombinant enzyme (10 ng) using H-Gly-Pro-AMC as a substrate. The competitive nature was estimated by plotting IC50 values measured at different substrate concentrations on the Y axis and substrate concentration on the X axis. The tight binding nature was estimated by plotting IC50 values measured at different plasma volumes on the Y axis and plasma volumes on the X axis. Fast binding kinetics was assessed by progressive curves at different inhibitor concentrations in the DPP-IV assay. The reversibility of the inhibitor was assessed by a dissociation study of the DPP-IV-sitagliptin complex. Durations of DPP-IV inhibition and efficacy were shown in ob/ob mice dosed at 10 mg/kg, p.o.
Sitagliptin is a competitive, reversible, fast and tight binding DPP-IV inhibitor. In ob/ob mice, 10 mg/kg, (p.o.) showed a long duration of inhibition of > 70% at 8 h. The duration was translated into long duration of efficacy (~ 35% glucose excursion at 8 h) in the same model and the effect was comparable to vildagliptin.
The DPP-IV inhibitor sitagliptin behaves as a competitive, tight, and fast binding inhibitor. Sitagliptin differs mechanistically from vildagliptin and exhibits comparable efficacy to that of latter. The finding may give an understanding to develop-second generation DPP-IV inhibitors with desired kinetic profiles.
Dipeptidyl peptidase-IV; fast binding inhibitor; sitagliptin; type 2 diabetes mellitus; vildagliptin
Saxagliptin, sitagliptin, and vildagliptin are dipeptidyl peptidase-4 (DPP-4) inhibitors widely approved for use in patients with type 2 diabetes. Using a crossover design, the present study compared trough levels of DPP-4 inhibition provided by these agents in a single cohort of patients with type 2 diabetes.
This was a randomized, placebo-controlled, open-label, five-period crossover study. Eligible patients were 18–65 years of age, either treatment-naïve or off prior antihyperglycemic agent therapy for at least 6 or 12 weeks (depending on the prior therapy), and had glycated hemoglobin (HbA1C) ≥6.5% and ≤10.0%. In separate study periods, patients received 5 mg saxagliptin q.d. (saxa-5), 100 mg sitagliptin q.d. (sita-100), 50 mg vildagliptin q.d. (vilda-50-q.d.), 50 mg vildagliptin b.i.d. (vilda-50-b.i.d.), or placebo for 5 days. The primary endpoint was trough %DPP-4 inhibition, derived by comparing DPP-4 activity 24 h after the Day-5 morning dose with predose activity in the same period and analyzed using a linear mixed-effects model with fixed-effects terms for treatment and period.
Mean (range) baseline HbA1C was 7.4% (6.4–9.0%; N = 22). Least-squares (LS) mean trough %DPP-4 inhibition was 73.5%, 91.7%, 28.9%, 90.6%, and 3.5% after saxa-5, sita-100, vilda-50-q.d., vilda-50-b.i.d., and placebo, respectively. In patients treated with sita-100, the LS-mean difference in trough %DPP-4 inhibition was 18.2% greater than with saxa-5 (p < 0.001), 62.9% greater than with vilda-50-q.d. (p < 0.001), 1.1% greater than with vilda-50-b.i.d. (p = 0.128), and 87.8% greater than with placebo (p < 0.001). Mean %DPP-4 inhibition was nearly maximal at 12 h postdose regardless of active treatment. Thus, these between-group comparisons at trough primarily reflected differences in duration of action. Adverse events reported during the study were transient and mild or moderate in intensity.
Once daily treatment with sitagliptin provided trough DPP-4 inhibition significantly greater than saxagliptin or vildagliptin administered once daily, and similar to that provided by vildagliptin administered twice daily.
Dipeptidyl peptidase-4; Enzyme inhibition; Saxagliptin; Sitagliptin; Type 2 diabetes; Vildagliptin
Given the scarcity of donors, moderately fatty livers (FLs) are currently being considered as possible grafts for orthotopic liver transplantation (OLT), notwithstanding their poor tolerance to conventional cold preservation. The behaviour of parenchymal and sinusoidal liver cells during transplantation is being studied worldwide. Much less attention has been paid to the biliary tree, although this is considered the Achille's heel even of normal liver transplantation. To evaluate the response of the biliary compartment of FLs to the various phases of OLT reliable markers are necessary. Previously we demonstrated that Alkaline Phosphatase was scarcely active in bile canaliculi of FLs and thus ruled it out as a marker. As an alternative, dipeptidylpeptidase-IV (DPP-IV), was investigated. This ecto-peptidase plays an important role in glucose metabolism, rapidly inactivating insulin secreting hormones (incretins) that are important regulators of glucose metabolism. DPP-IV inhibitors are indeed used to treat Type II diabetes. Neuropeptides regulating bile transport and composition are further important substrates of DPP-IV in the enterohepatic axis. DPP-IV activity was investigated with an azo-coupling method in the liver of fatty Zucker rats (fa/fa), using as controls lean Zucker (fa/+) and normal Wistar rats. Protein expression was studied by immunofluorescence with the monoclonal antibody (clone 5E8). In Wistar rat liver, DPP-IV activity and expression were high in the whole biliary tree, and moderate in sinusoid endothelial cells, in agreement with the literature. Main substrates of DPP-IV in hepatocytes and cholangiocytes could be incretins GLP-1 and GIP, and neuropeptides such as vasoactive intestinal peptide (VIP) and substance P, suggesting that these substances are inactivated or modified through the biliary route. In lean Zucker rat liver the enzyme reaction and protein expression patterns were similar to those of Wistar rat. In obese rat liver the patterns of DPP-IV activity and expression in hepatocytes reflected the morphological alterations induced by steatosis as lipid-rich hepatocytes had scarce activity, located either in deformed bile canaliculi or in the sinusoidal and lateral domains of the plasma membrane. These findings suggest that bile canaliculi in steatotic cells have an impaired capacity to inactivate incretins and neuropeptides. Incretin and/or neuropeptide deregulation is indeed thought to play important roles in obesity and insulin-resistance. No alteration in enzyme activity and expression was found in the upper segments of the biliary tree of obese respect to lean Zucker and Wistar rats. In conclusion, this research demonstrates that DPP-IV is a promising in situ marker of biliary functionality not only of normal but also of fatty rats. The approach, initially devised to investigate the behaviour of the liver during the various phases of transplantation, appears to have a much higher potentiality as it could be further exploited to investigate any pathological or stressful conditions involving the biliary tract (i.e., metabolic syndrome and cholestasis) and the response of the biliary tract to therapy and/or to surgery.
Dipeptidylpeptidase-IV; fatty liver; incretins; neuropeptides; biliary tree; bile canaliculi; hepatocytes.
There has been great interest in determining whether natural products show biological activity toward protein targets of pharmacological relevance. One target of particular interest is DPP-IV whose most important substrates are incretins that, among other beneficial effects, stimulates insulin biosynthesis and secretion. Incretins have very short half-lives because of their rapid degradation by DPP-IV and, therefore, inhibiting this enzyme improves glucose homeostasis. As a result, DPP-IV inhibitors are of considerable interest to the pharmaceutical industry. The main goals of this study were (a) to develop a virtual screening process to identify potential DPP-IV inhibitors of natural origin; (b) to evaluate the reliability of our virtual-screening protocol by experimentally testing the in vitro activity of selected natural-product hits; and (c) to use the most active hit for predicting derivatives with higher binding affinities for the DPP-IV binding site.
We predicted that 446 out of the 89,165 molecules present in the natural products subset of the ZINC database would inhibit DPP-IV with good ADMET properties. Notably, when these 446 molecules were merged with 2,342 known DPP-IV inhibitors and the resulting set was classified into 50 clusters according to chemical similarity, there were 12 clusters that contained only natural products for which no DPP-IV inhibitory activity has been previously reported. Nine molecules from 7 of these 12 clusters were then selected for in vitro activity testing and 7 out of the 9 molecules were shown to inhibit DPP-IV (where the remaining two molecules could not be solubilized, preventing the evaluation of their DPP-IV inhibitory activity). Then, the hit with the highest activity was used as a lead compound in the prediction of more potent derivatives.
We have demonstrated that our virtual-screening protocol was successful in identifying novel lead compounds for developing more potent DPP-IV inhibitors.
Glucagon-like peptide 1 (GLP-1) agonists improve myocardial function and insulin sensitivity in the setting of chronic heart failure. Endogenously produced GLP-1 peptide (7-36) is rapidly cleaved by dipeptidyl peptidase 4 (DPP4) to the 9-36 peptide, which lacks anti-hyperglycemic activity. To elucidate the effect of increased endogenous GLP-1 during heart failure progression, the DPP4 inhibitor saxagliptin or vehicle was administered by daily oral gavage to female TG9 mice, a transgenic model of dilated cardiomyopathy, starting at day of life 42, just prior to the development of detectable contractile dysfunction. Saxagliptin treatment inhibited DPP4 activity >90% and increased GLP-1 levels 4-fold following a 2 gm/kg glucose load but did not affect fasting GLP-1 levels. There was no difference in food intake or body weight between groups. At 56 days of age, oral glucose tolerance was improved in saxagliptin-versus vehicle-treated animals (AUC0-120 1340 ± 46 and 1501 ± 43 min·mmol/L, respectively, p<0.015). In contrast to the effect of a GLP-1 agonist in TG9 mice, saxagliptin had no effect on survival (80.7 ± 4.3 days) compared to vehicle-treated mice (79.6 ± 3.6 days, p = 0.46). Taken together, these data indicate that improvement in glucose tolerance is not sufficient to improve survival. Future efforts to confirm these findings in additional models of heart failure are warranted.
cardiac function; insulin sensitivity; mouse model; glucose transport; incretin hormone
Progressive remodeling after myocardial infarction (MI) is a leading cause of morbidity and mortality. Recently, glucagon-like peptide (GLP)-1 was shown to have cardioprotective effects, but treatment with GLP-1 is limited by its short half-life. It is rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4), an enzyme which inhibits GLP-1 activity. We hypothesized that the DPP-4 inhibitor vildagliptin will increase levels of GLP-1 and may exert protective effects on cardiac function after MI.
Sprague-Dawley rats were either subjected to coronary ligation to induce MI and left ventricular (LV) remodeling, or sham operation. Parts of the rats with an MI were pre-treated for 2 days with the DPP-4 inhibitor vildagliptin (MI-Vildagliptin immediate, MI-VI, 15 mg/kg/day). The remainder of the rats was, three weeks after coronary artery ligation, subjected to treatment with DPP-4 inhibitor vildagliptin (MI-Vildagliptin Late, MI-VL) or control (MI). At 12 weeks, echocardiography and invasive hemodynamics were measured and molecular analysis and immunohistochemistry were performed.
Vildagliptin inhibited the DPP-4 enzymatic activity by almost 70% and increased active GLP-1 levels by about 3-fold in plasma in both treated groups (p < 0.05 vs. non-treated groups). Cardiac function (ejection fraction) was decreased in all 3 MI groups compared with Sham group (p < 0.05); treatment with vildagliptin, either early or late, did not reverse cardiac remodeling. ANP (atrial natriuretic peptide) and BNP (brain natriuretic peptide) mRNA levels were significantly increased in all 3 MI groups, but no significant reductions were observed in both vildagliptin groups. Vildagliptin also did not change cardiomyocyte size or capillary density after MI. No effects were detected on glucose level and body weight in the post-MI remodeling model.
Vildagliptin increases the active GLP-1 level via inhibition of DPP-4, but it has no substantial protective effects on cardiac function in this well established long-term post-MI cardiac remodeling model.
vildagliptin; myocardial infarction; cardiac remodeling; heart failure; diabetes
The gut incretin glucagon-like peptide-1 (GLP-1) and the intestinotropic hormone GLP-2 are released from enteroendocrine L cells in response to ingested nutrients. Treatment with an exogenous GLP-2 analogue increases intestinal villous mass and prevents intestinal injury. Since GLP-2 is rapidly degraded by dipeptidyl peptidase 4 (DPP4), DPP4 inhibition may be an effective treatment for intestinal ulcers. We measured mRNA expression and DPP enzymatic activity in intestinal segments. Mucosal DPP activity and GLP concentrations were measured after administration of the DPP4 inhibitor sitagliptin (STG). Small intestinal ulcers were induced by indomethacin (IM) injection. STG was given before IM treatment, or orally administered after IM treatment with or without an elemental diet (ED). DPP4 mRNA expression and enzymatic activity were high in the jejunum and ileum. STG dose-dependently suppressed ileal mucosal enzyme activity. Treatment with STG prior to IM reduced small intestinal ulcer scores. Combined treatment with STG and ED accelerated intestinal ulcer healing, accompanied by increased mucosal GLP-2 concentrations. The reduction of ulcers by ED and STG was reversed by co-administration of the GLP-2 receptor antagonist. DPP4 inhibition combined with luminal nutrients, which up-regulate mucosal concentrations of GLP-2, may be an effective therapy for the treatment of small intestinal ulcers.
GLP-1; GLP-2; DPP4; DPP8; sitagliptin
Dipeptidyl peptidase IV (DPP-IV) inhibition to modulate the incretin effect is a proven strategy to treat type 2 diabetes mellitus. The present study describes the pharmacological profile of a novel DPP-IV inhibitor RBx-0128, as an antidiabetic agent.
Material and Methods:
DPP-IV assay was carried out to evaluate in vitro potency of RBx-0128 using human, mouse, and rat plasma as an enzyme source. Selectivity was assessed with various serine proteases. In vivo efficacy was assessed in ob/ob mice. The pharmacokinetic (PK) profile was performed in Wistar rats.
RBx-0128 inhibited human, mouse, and rat plasma DPP-IV activity with IC50 values of 10.6, 18.1, and 56.0 nM respectively, selective over various serine proteases (900–9000-fold). The inhibition was reversible and competitive in nature. In ob/ob mice, RBx-0128 significantly (P < 0.05) inhibited plasma DPP-IV and stimulated GLP-1 and insulin at 10 mg/kg. In the oral glucose tolerance test (OGTT), glucose lowering effect was better than sitagliptin (23 vs. 17%) at 10 mg/kg. The effect was sustained till 8 hours (30-35%) at 10 mg/kg with favorable PK profile (plasma clearance: 39.3 ml/min/kg; Cmax 790 ng/ml; t1/2 1.6 hours; tmax 4.8 hours, Vss 3.24 l/kg and Foral 55%) in Wistar rats.
The present study showed that RBx-0128 is a novel, DPP-IV inhibitor with an antihyperglycemic effect. It can be a promising candidate for the treatment of type 2 diabetes mellitus.
Antidiabetic effect; dipeptidyl peptidase-IV inhibitor; glucagon-like peptide-1; oral glucose tolerance test; sitagliptin
Type 2 diabetes mellitus (DM) is a prevalent disorder that affects children, adolescents, and adults worldwide. In addition to risks of microvascular disease, patients with type 2 DM often have multiple risk factors of macrovascular disease; for example, approximately 90% of patients with type 2 DM are overweight/obese. Type 2 DM is a complex disease that involves a variety of pathophysiologic abnormalities, including insulin resistance, increased hepatic glucose production, and abnormalities in the secretion of hormones, such as insulin, glucagon, amylin, and incretins. Incretins are gut-derived peptides with a variety of glucoregulatory functions. Incretin dysfunction can be treated with glucagon-like peptide 1 (GLP-1) receptor agonists (eg, exenatide and liraglutide) or inhibitors of dipeptidyl peptidase 4 (DPP-4) (eg, sitagliptin and saxagliptin), the enzyme that degrades GLP-1. The GLP-1 receptor agonists and DPP-4 inhibitors both elevate GLP-1 activity and substantially improve glycemic control. The GLP-1 receptor agonists are more effective in lowering blood glucose and result in substantial weight loss, whereas therapy with DPP-4 inhibitors lowers blood glucose levels to a lesser degree, and they are weight neutral. Treatment with GLP-1 receptor agonists has demonstrated durable glycemic control and improvement in multiple cardiovascular disease risk factors. In addition, unlike insulin or sulfonylureas, treatment with a GLP-1 receptor agonist or a DPP-4 inhibitor has not been associated with substantial hypoglycemia. These factors should be considered when selecting monotherapy or elements of combination therapy for patients with type 2 DM who are overweight/obese, for patients who have experienced hypoglycemia with other agents, and when achieving glycemic targets is difficult.
Type 2 diabetes (T2D) is associated with reduction and dysfunction of circulating pro-angiogenic cells (PACs). DPP-4 inhibitors, a class of oral agents for T2D, might possess pleiotropic vasculoprotective activities. Herein, we tested whether DPP-4 inhibition with Saxagliptin affects the function of circulating PACs from T2D and healthy subjects.
PACs were isolated from T2D (n = 20) and healthy (n = 20) subjects. Gene expression, clonogenesis, proliferation, adhesion, migration and tubulisation were assessed in vitro by incubating PACs with or without Saxagliptin and SDF-1α. Stimulation of angiogenesis by circulating cells from T2D patients treated with Saxagliptin or other non-incretinergic drugs was assessed in vivo using animal models.
Soluble DPP-4 activity was predominant over cellular activity and was successfully inhibited by Saxagliptin. At baseline, T2D compared to healthy PACs contained less acLDL+Lectin+ cells, and showed altered expression of genes related to adhesion and cell cycle regulation. This was reflected by impaired adhesion and clonogenesis/proliferative response of T2D PACs. Saxagliptin + SDF-1α improved adhesion and tube sustaining capacity of PACs from T2D patients. CD14+ PACs were more responsive to Saxagliptin than CD14- PACs. While Saxagliptin modestly reduced angiogenesis by mature endothelial cells, circulating PACs-progeny cells from T2D patients on Saxagliptin treatment displayed higher growth factor-inducible in vivo angiogenetic activity, compared to cells from T2D patients on non-incretinergic regimen.
Saxagliptin reverses PACs dysfunction associated with T2D in vitro and improves inducible angiogenesis by circulating cells in vivo. These data add knowledge to the potential pleiotropic cardiovascular effects of DPP-4 inhibition.
Regeneration; Stem cells; Angiogenesis; Cardiovascular disease
Incretins are gut hormones that are secreted from enteroendocrine cells into the blood within minutes after eating. One of their many physiological roles is to regulate the amount of insulin that is secreted after eating. In this manner, as well as others to be described in this review, their final common raison d’être is to aid in disposal of the products of digestion. There are two incretins, known as glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1), that share many common actions in the pancreas but have distinct actions outside of the pancreas. Both incretins are rapidly deactivated by an enzyme called dipeptidyl peptidase 4 (DPP4). A lack of secretion of incretins or an increase in their clearance are not pathogenic factors in diabetes. However, in type 2 diabetes (T2DM), GIP no longer modulates glucose-dependent insulin secretion, even at supraphysiological (pharmacological) plasma levels, and therefore GIP incompetence is detrimental to β-cell function, especially after eating. GLP-1, on the other hand, is still insulinotropic in T2DM, and this has led to the development of compounds that activate the GLP-1 receptor with a view to improving insulin secretion. Since 2005, two new classes of drugs based on incretin action have been approved for lowering blood glucose levels in T2DM: an incretin mimetic (exenatide, which is a potent long-acting agonist of the GLP-1 receptor) and an incretin enhancer (sitagliptin, which is a DPP4 inhibitor). Exenatide is injected subcutaneously twice daily and its use leads to lower blood glucose and higher insulin levels, especially in the fed state. There is glucose-dependency to its insulin secretory capacity, making it unlikely to cause low blood sugars (hypoglycemia). DPP4 inhibitors are orally active and they increase endogenous blood levels of active incretins, thus leading to prolonged incretin action. The elevated levels of GLP-1 are thought to be the mechanism underlying their blood glucose-lowering effects.
Many medicines, including several cholesterol-lowering agents (eg, lovastatin, simvastatin), antihypertensives (eg, diltiazem, nifedipine, verapamil), and antifungals (eg, ketoconazole) are metabolized by and/or inhibit the cytochrome P450 (CYP) 3A4 metabolic pathway. These types of medicines are commonly coprescribed to treat comorbidities in patients with type 2 diabetes mellitus (T2DM) and the potential for drug-drug interactions of these medicines with new medicines for T2DM must be carefully evaluated.
To investigate the effects of CYP3A4 substrates or inhibitors, simvastatin (substrate), diltiazem (moderate inhibitor), and ketoconazole (strong inhibitor) on the pharmacokinetics and safety of saxagliptin, a CYP3A4/5 substrate; and the effects of saxagliptin on these agents in three separate studies.
Healthy subjects were administered saxagliptin 10 mg or 100 mg. Simvastatin, diltiazem extended-release, and ketoconazole doses of 40 mg once daily, 360 mg once daily, and 200 mg twice daily, respectively, were used to determine two-way pharmacokinetic interactions.
Coadministration of simvastatin, diltiazem extended-release, or ketoconazole increased mean area under the concentration-time curve values (AUC) of saxagliptin by 12%, 109%, and 145%, respectively, versus saxagliptin alone. Mean exposure (AUC) of the CYP3A4-generated active metabolite of saxagliptin, 5-hydroxy saxagliptin, decreased with coadministration of simvastatin, diltiazem, and ketoconazole by 2%, 34%, and 88%, respectively. All adverse events were considered mild or moderate in all three studies; there were no serious adverse events or deaths.
Saxagliptin, when coadministered with simvastatin, diltiazem extended-release, or ketoconazole, was safe and generally well tolerated in healthy subjects. Clinically meaningful interactions of saxagliptin with simvastatin and diltiazem extended-release are not expected. The dose of saxagliptin does not need to be adjusted when coadministered with a substrate or moderate inhibitor of CYP3A4. A limitation to the lowest clinical dose of saxagliptin (2.5 mg) is proposed when it is coadministered with a potent CYP3A4 inhibitor such as ketoconazole.
cytochrome P450 3A4/5; diltiazem extended-release; ketoconazole; pharmacokinetics; simvastatin; type 2 diabetes mellitus
Dipeptidyl‐peptidase 4 (DPP4) inhibitors improve glycemic control in patients with diabetes mellitus by preventing the degradation of glucagon‐like peptide‐1 (GLP‐1). GLP‐1 causes vasodilation in animal models but also increases sympathetic activity; the effect of GLP‐1 in the human vasculature and how it is altered by DPP4 inhibition is not known. DPP4 also degrades the vasodilator brain natriuretic peptide (BNP) to a less potent metabolite. This study tested the hypothesis that DPP4 inhibition potentiates the vasodilator responses to GLP‐1 and BNP in the human forearm.
Method and Results
Seventeen healthy subjects participated in this randomized, double‐blinded, placebo‐controlled crossover study. On each study day, subjects received DPP4 inhibitor (sitagliptin 200 mg by mouth) or placebo. Sitagliptin increased forearm blood flow and decreased forearm vascular resistance without affecting mean arterial pressure and pulse. GLP‐1 and BNP were infused in incremental doses via brachial artery. Venous GLP‐1 concentrations were significantly higher during sitagliptin use, yet there was no effect of GLP‐1 on forearm blood flow in the presence or absence of sitagliptin. BNP caused dose‐dependent vasodilation; however, sitagliptin did not affect this response. GLP‐1 and BNP had no effect on net norepinephrine release.
These data suggest that GLP‐1 does not act as a direct vasodilator in humans and does not contribute to sympathetic activation. Sitagliptin does not regulate vascular function in healthy humans by affecting the degradation of GLP‐1 and BNP.
Clinical Trial Registration
URL: www.clinicaltrials.gov/ Unique identifier: NCT01413542.
diabetes mellitus; dipeptidyl‐peptidase 4; glucagon‐like peptide‐1; natriuretic peptide; vasodilation
Glucagon-like peptide-1 (7-36)amide (GLP-1) is cleaved by dipeptidyl peptidase-4 (DPP-4) to GLP-1 (9-36)amide. We examined whether chemical inhibition or genetic elimination of DPP-4 activity affects cardiovascular function in normoglycemic and diabetic mice after experimental myocardial infarction.
RESEARCH DESIGN AND METHODS
Cardiac structure and function was assessed by hemodynamic monitoring and echocardiography in DPP-4 knockout (Dpp4−/−) mice versus wild-type (Dpp4+/+) littermate controls and after left anterior descending (LAD) coronary artery ligation–induced myocardial infarction (MI). Effects of sustained DPP-4 inhibition with sitagliptin versus treatment with metformin were ascertained after experimental MI in a high-fat diet–streptozotocin model of murine diabetes. Functional recovery from ischemia-reperfusion (I/R) injury was measured in isolated hearts from Dpp4−/− versus Dpp4+/+ littermates and from normoglycemic wild-type (WT) mice treated with sitagliptin or metformin. Cardioprotective signaling in the murine heart was examined by RT-PCR and Western blot analyses.
Dpp4−/− mice exhibited normal indexes of cardiac structure and function. Survival post-MI was modestly improved in normoglycemic Dpp4−/− mice. Increased cardiac expression of phosphorylated AKT (pAKT), pGSK3β, and atrial natriuretic peptide (ANP) was detected in the nonischemic Dpp4−/− heart, and HO-1, ANP, and pGSK3β proteins were induced in nonischemic hearts from diabetic mice treated with sitagliptin or metformin. Sitagliptin and metformin treatment of wild-type diabetic mice reduced mortality after myocardial infarction. Sitagliptin improved functional recovery after I/R injury ex vivo in WT mice with similar protection from I/R injury also manifest in hearts from Dpp4−/− versus Dpp4+/+ mice.
Genetic disruption or chemical inhibition of DPP-4 does not impair cardiovascular function in the normoglycemic or diabetic mouse heart.
Glucagon-like peptide-1(7–36)amide (GLP-1) is a secreted peptide that acts as a key determinant of blood glucose homeostasis by virtue of its abilities to slow gastric emptying, to enhance pancreatic insulin secretion, and to suppress pancreatic glucagon secretion. GLP-1 is secreted from L cells of the gastrointestinal mucosa in response to a meal, and the blood glucose-lowering action of GLP-1 is terminated due to its enzymatic degradation by dipeptidyl-peptidase-IV (DPP-IV). Released GLP-1 activates enteric and autonomic reflexes while also circulating as an incretin hormone to control endocrine pancreas function. The GLP-1 receptor (GLP-1R) is a G protein-coupled receptor that is activated directly or indirectly by blood glucose-lowering agents currently in use for the treatment of type 2 diabetes mellitus (T2DM). These therapeutic agents include GLP-1R agonists (exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, and langlenatide) and DPP-IV inhibitors (sitagliptin, vildagliptin, saxagliptin, linagliptin, and alogliptin). Investigational agents for use in the treatment of T2DM include GPR119 and GPR40 receptor agonists that stimulate the release of GLP-1 from L cells. Summarized here is the role of GLP-1 to control blood glucose homeo-stasis, with special emphasis on the advantages and limitations of GLP-1-based therapeutics.
Diphenylpyraline hydrochloride (DPP) is an internationally available antihistamine that produces therapeutic antiallergic effects by binding to histamine H1 receptors. The complete neuropharmacological and behavioral profile of DPP, however, remains uncharacterized. Here we describe studies that suggest DPP may fit the profile of a potential agonist replacement medication for cocaine addiction. Aside from producing the desired histamine reducing effects, many antihistamines can also elicit psychomotor activation and reward, both of which are associated with increased dopamine concentrations in the nucleus accumbens (NAc). The primary aim of this study was to investigate the potential ability of DPP to inhibit the dopamine transporter, thereby leading to elevated dopamine concentrations in the NAc in a manner similar to cocaine and other psychostimulants. The psychomotor activating and rewarding effects of DPP were also investigated. For comparative purposes cocaine, a known dopamine transporter inhibitor, psychostimulant and drug of abuse, was used as a positive control. As predicted, both cocaine (15 mg/kg) and an equimolar dose of DPP (14 mg/kg) significantly inhibited dopamine uptake in the NAc in vivo and produced locomotor activation, although the time-course of pharmacological effects of the two drugs was different. In comparison to cocaine, DPP showed a prolonged effect on dopamine uptake and locomotion. Furthermore, cocaine, but not DPP, produced significant conditioned place preference, a measure of drug reward. The finding that DPP functions as a potent dopamine uptake inhibitor without producing significant rewarding effects suggests that DPP merits further study as a potential candidate as an agonist pharmacotherapy for cocaine addiction.
agonist therapy; reward; psychostimulant; antihistamine; benztropine; dopamine
The oral DPP-4 inhibitors are new incretin-based therapies for treatment of type 2 diabetes. To assess the efficacy and safety of three DPP-4 inhibitors (Saxagliptin, Sitagliptin and Vildagliptin) as add-on therapy to dual combination of traditional oral hypoglycemic agents in Chinese type 2 diabetes patients.
In this 24-week, randomized, open-label, parallel clinical trial, we enrolled inadequately controlled (glycosylated haemoglobin A1c [HbA1c] ≥7.5% to ≤10%) patients with type 2 diabetes, who were treated by dual combination of metformin and another traditional oral hypoglycemic agent (glimepiride, acarbose or pioglitazone). 207 patients had been randomized to add-on 5 mg saxagliptin group or 100 mg sitagliptin once daily group, or 50 mg vildagliptin twice daily group for 24 weeks. HbA1c, fasting and postprandial blood glucose (FBG and P2hBG), body weight, body mass index (BMI), episodes of hypoglycemia and adverse events were evaluated.
After 24 weeks, HbA1c, FBG, and P2hBG of each group were significantly decreased. (saxagliptin vs vildagliptin vs sitagliptin: HbA1c: -1.2% vs -1.3% vs -1.1%; FBG: -1.8 mmol/l vs -2.4 mmol/l vs -1.5 mmol/l; P2hBG: -3.4 mmol/l vs -3.7 mmol/l vs -3.2 mmol/l). The changes of HbA1c and P2hBG among the three groups had no significance. However, vildagliptin-added group showed the greatest reduction (p < 0.001), while, sitagliptin-added group showed the lowest reduction (p < 0.001) in terms of FPG changes. Proportions of patients achieving HbA1c < 7% at the end were similar in three groups (saxagliptin 59%, vildagliptin 65%, sitagliptin 59%). Mild hypoglycemia was commonly reported among the three groups (saxagliptin 6%, vildagliptin 2%, sitagliptin 3%). No significant between-group difference was shown in other AEs.
The three gliptins showed almost similar glycemic control and incidence of adverse events. However, for FBG control, saxagliptin demonstrated superiority to sitagliptin, while, inferiority to vildagliptin.
Type 2 diabetes mellitus; Glycemic control; DPP-4 inhibitors; OHAs
To compare the safety and efficacy of the dipeptidylpeptidase-4 (DPP-4) inhibitors in patients with type 2 diabetes and inadequate glycemic control.
Systematic review of randomized controlled trials (RCTs), health economic evaluation studies, systematic reviews, and meta-analyses, followed by primary Bayesian mixed treatment comparison meta-analyses (MTCs), and secondary frequentist direct-comparison meta-analyses using a random-effects model. Outcomes were reported as weighted mean change from baseline, or odds ratio (OR) with 95% credible interval.
MEDLINE, MEDLINE In-Process, EMBASE, and BIOSIS via Dialog ProQuest; Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews via EBSCO; four diabetes and two technical congress abstracts; and health technology assessment organization websites.
Patients with type 2 diabetes and inadequate glycemic control receiving any pharmacological anti-diabetic treatment.
Data extraction and analysis
Title/abstracts were reviewed for eligibility, followed by full-text review of publications remaining after first pass. A three-person team filtered articles and an independent reviewer checked a random selection (10%) of filtered articles. Data extraction and quality assessment of studies were also independently reviewed. Five DPP-4 inhibitors (alogliptin, linagliptin, saxagliptin, sitagliptin, and vildagliptin) were compared via meta-analysis (where data were available) as monotherapy, dual therapy (plus metformin, sulfonylurea, pioglitazone, or insulin), and triple therapy (plus metformin/sulfonylurea).
The review identified 6,601 articles; 163 met inclusion criteria and 85 publications from 83 RCTs contained sufficient or appropriate data for analysis. MTCs demonstrated no differences between DPP-4 inhibitors in mean change from baseline in glycosylated hemoglobin (HbA1c) or body weight, or the proportions of patients achieving HbA1c <7% or experiencing a hypoglycemic event, apart from in patients on alogliptin plus metformin, who achieved HbA1c <7% more frequently than those treated with saxagliptin plus metformin [OR 6.41 (95% CI 3.15–11.98) versus 2.17 (95% CI 1.56–2.95)].
This systematic review and MTC showed similar efficacy and safety for DPP-4 inhibitors as treatment for type 2 diabetes, either as monotherapy or combination therapy.
Electronic supplementary material
The online version of this article (doi:10.1007/s13300-014-0061-3) contains supplementary material, which is available to authorized users.
Alogliptin; DPP-4 inhibitor; Glycosylated hemoglobin; Linagliptin; Mixed treatment comparison; Saxagliptin; Sitagliptin; Type 2 diabetes mellitus; Vildagliptin