The dipeptidylpeptidase‐IV inhibitors sitagliptin,vildagliptin and saxagliptin do not impair innate and adaptive immune responses

Inhibitors of dipeptidylpeptidase IV (DPP‐IV) represent a novel class of frequently used anti‐diabetic drugs. In addition to its function in metabolic regulation, DPP‐IV also plays a role in the immune system. Whether the DPP‐IV inhibitors sitagliptin, vildagliptin or saxagliptin impair immune responses is, however, currently unknown. Here, we investigated the effect of these agents on both innate and adaptive immunity. We found that the DPP‐IV inhibitors did not affect the innate immune response induced by Toll‐like receptor (TLR) ligands, as cytokine secretion and induction of co‐stimulatory molecules by human blood mononuclear cells was not impaired. Furthermore, proliferation of T cells and suppressive function of regulatory T cells was preserved. Mice treated with vildagliptin showed normal cytokine production, immune cell activation and lymphocyte trafficking upon TLR activation. Thus, crucial immunological parameters remain unaffected upon treatment with DPP‐IV inhibitors, a fact that is reassuring with respect to safety of these drugs.     

Synergistic effect of α‐glucosidase inhibitors and dipeptidyl peptidase 4 inhibitor treatment

Monotherapy of α‐glucosidase inhibitor (α‐GI) or dipeptidyl peptidase 4 (DPP4) inhibitor does not sufficiently minimize glucose fluctuations in the diabetic state. In the present study, we evaluated the combined effects of various of α‐GI inhibitors (acarbose, voglibose or miglitol) and sitagliptin, a DPP4 inhibitor, on blood glucose fluctuation, insulin and active glucagon‐like peptide‐1 (GLP‐1) levels after nutriment loading in mice. Miglitol and sitagliptin elicited a 47% reduction (P < 0.05) of the area under the curve of blood glucose levels for up to 2 h after maltose‐loading, a 60% reduction (P < 0.05) in the range of blood glucose fluctuation, and a 32% decrease in plasma insulin compared with the control group. All three of the combinations elicited a 2.5–4.9‐fold synergistic increase in active GLP‐1 (P < 0.05 vs control). Thus, combined treatment with the α‐GI miglitol, which more strongly inhibits the early phase of postprandial hyperglycemia, and DPP4 inhibitor yields both complementary and synergistic effects, and might represent a superior anti‐hyperglycemic therapy. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00081.x, 2011)     

Dipeptidyl peptidase-4 inhibitors and HbA1c target of <7% in type 2 diabetes: meta-analysis of randomized controlled trials

Aim: We assessed the efficacy of dipeptidyl peptidase‐4 (DPP‐4) inhibitors vildagliptin, sitagliptin, saxagliptin and alogliptin to reach the haemoglobin HbA1c target of <7% in people with type 2 diabetes. Methods: We conducted an electronic search for randomized controlled trials (RCTs) involving DPP‐4 inhibitors through September 2010. RCTs were included if they lasted at least 12 weeks, included 30 patients or more and reported the proportion of patients reaching the HbA1c target of <7%. Results: A total of 43 RCTs reporting 52 comparisons met the selection criteria, which included 19 101 study participants evaluated for the primary endpoint, 10 467 treated with a DPP‐4 inhibitor and 8634 treated with placebo or a comparator drug. DPP‐4 inhibitors showed a statistically significant reduction in HbA1c compared to placebo and approximately 40% of participants achieved the HbA1c goal of <7%: this was associated with weight neutrality and no greater hypoglycaemia. The reduction of the HbA1c level and the rate of HbA1c goal attainment was not different from comparator drugs, with similar hypoglycaemia, and different effect on weight owing to the nature of comparator (metformin, sulfonylurea or glitazones). Baseline HbA1c was the best predictor for achievement of A1C target (overall weighted r² value = 0.410, p < 0.001). Conclusions: A greater proportion of type 2 diabetic patients can achieve the HbA1c goal <7% with DPP‐4 inhibitors compared to placebo, with no weight gain, and no hypoglycaemic risk when used alone; DPP‐4 inhibitors were not different from comparator drugs.     

Longer term safety of dipeptidyl peptidase‐4 inhibitors in patients with type 2 diabetes mellitus: systematic review and meta‐analysis

Dipeptidyl peptidase‐4 (DPP‐4) inhibitors are oral antidiabetic agents that hold the potential of slowing the progress of type 2 diabetes mellitus. Their long‐term safety is still a subject of debate. A systematic review of randomized, controlled trials was undertaken to comprehensively profile the safety of chronic treatment of type 2 diabetes mellitus with DPP‐4 inhibitors. We searched data sources including MEDLINE, CENTRAL, publishers' and manufacturers' databases. Eligible trials were double‐blind, randomized, placebo or active‐controlled trials with ≥18 weeks duration in patients with type 2 diabetes reporting safety outcomes. Meta‐analysis was performed separately for trials in which the control group received placebo (44 studies), another gliptin (3 studies) and any other antidiabetic drug (20 studies). Risk ratios with 95% confidence intervals were computed using a Mantel‐Haenszel fixed‐effect model for general safety outcomes, hypoglycaemia and adverse events by system organ class. Of 307 publications retrieved, 67 randomized, controlled trials met the eligibility criteria and were included in this review (4 alogliptin, 8 linagliptin, 8 saxagliptin, 20 sitagliptin, and 27 vildagliptin trials). Adverse events with gliptin treatment were at placebo level (relative risk (RR) 1.02 [0.99, 1.04]). No increased risk of infections was detectable (RR 0.98 [0.93, 1.05] compared to placebo and 1.02 [0.97, 1.07] compared to other antidiabetic drugs). Asthenia (RR 1.57 [1.09, 2.27]) as well as cardiac (RR 1.37 [1.00, 1.89]) and vascular disorders (RR 1.74 [1.05, 2.86] for linagliptin) emerged as adverse events associated with DPP‐4 inhibitor treatment. The risk of hypoglycaemia was low with DPP‐4 inhibitor treatment (RR 0.92 [0.74, 1.15] compared to placebo, RR 0.20 [0.17, 0.24] compared to sulphonylureas) in the absence of sulphonylurea or insulin co‐therapy, but significantly elevated for combination therapy of sulphonylurea or insulin with sitagliptin or linagliptin (RR 1.86 [1.46, 2.37] compared to placebo). A large body of data supports the long‐term safety of gliptin treatment and refutes an increased risk of infections. Further research is needed to clarify a possible link to asthenia, cardiac and vascular events. For combination therapy with insulin or insulin secretagogues, a careful choice of the agent used may limit the risk of hypoglycaemia.     

Pharmacokinetics of dipeptidylpeptidase‐4 inhibitors

Type 2 diabetes (T2DM) is a complex disease combining defects in insulin secretion and insulin action. New compounds have been developed for improving glucose‐induced insulin secretion and glucose control, without inducing hypoglycaemia or weight gain. Dipeptidylpeptidase‐4 (DPP‐4) inhibitors are new oral glucose‐lowering agents, so‐called incretin enhancers, which may be used as monotherapy or in combination with other antidiabetic compounds. Sitagliptin, vildaglipin and saxagliptin are already on the market in many countries, either as single agents or in fixed‐dose combined formulations with metformin. Other DPP‐4 inhibitors, such as alogliptin and linagliptin, are currently in late phase of development. The present paper summarizes and compares the main pharmacokinetics (PK) properties, that is, absorption, distribution, metabolism and elimination, of these five DPP‐4 inhibitors. Available data were obtained in clinical trials performed in healthy young male subjects, patients with T2DM, and patients with either renal insufficiency or hepatic impairment. PK characteristics were generally similar in young healthy subjects and in middle‐aged overweight patients with diabetes. All together gliptins have a good oral bioavailability which is not significantly influenced by food intake. PK/pharmacodynamics characteristics, that is, sufficiently prolonged half‐life and sustained DPP‐4 enzyme inactivation, generally allow one single oral administration per day for the management of T2DM; the only exception is vildagliptin for which a twice‐daily administration is recommended because of a shorter half‐life. DPP‐4 inhibitors are in general not substrates for cytochrome P450 (except saxagliptin that is metabolized via CYP 3A4/A5) and do not act as inducers or inhibitors of this system. Several metabolites have been documented but most of them are inactive; however, the main metabolite of saxagliptin also exerts a significant DPP‐4 inhibition and is half as potent as the parent compound. Renal excretion is the most important elimination pathway, except for linagliptin whose metabolism in the liver appears to be predominant. PK properties of gliptins, combined with their good safety profile, explain why no dose adjustment is necessary in elderly patients or in patients with mild to moderate hepatic impairment. As far as patients with renal impairment are concerned, significant increases in drug exposure for sitagliptin and saxagliptin have been reported so that appropriate reductions in daily dosages are recommended according to estimated glomerular filtration rate. The PK characteristics of DPP‐4 inhibitors suggest that these compounds are not exposed to a high risk of drug–drug interactions. However, the daily dose of saxagliptin should be reduced when coadministered with potent CYP 3A4 inhibitors. In conclusion, besides their pharmacodynamic properties leading to effective glucose‐lowering effect without inducing hypoglycaemia or weight gain, DPP‐4 inhibitors show favourable PK properties, which contribute to a good efficacy/safety ratio for the management of T2DM in clinical practice.     

Adverse effects of dipeptidyl peptidases 8 and 9 inhibition in rodents revisited

Aim: To evaluate the association between inhibition of dipeptidyl peptidase (DPP)‐8 and/or DPP‐9 organ toxicities and mortality in rodents. Research Design and Methods: The relative selectivity of the DPP‐4 inhibitor, vildagliptin, was determined by comparing its K_I (concentration of compound yielding 50% inhibition of the enzyme) values for inhibition of recombinant human DPP‐4, DPP‐8 and DPP‐9 assessed in vitro. In experiments performed in vivo, vildagliptin was administered by gavage for 13 weeks, at doses up to 1500 mg/kg/day in CD‐1 mice and at doses up to 900 mg/kg/day in Wistar rats. Plasma concentrations of vildagliptin were assessed at week 12, and toxicities previously ascribed to inhibition of DPP‐8 and/or DPP‐9 were assessed at week 13. Results: The K_I values for vildagliptin‐induced inhibition of DPP‐4, DPP‐8 and DPP‐9 were 3, 810 and 95 nM respectively. The mean plasma concentration 24 h after dose after 12‐week daily dosing with 1500 mg/kg/day in mice was 2279 nM. The mean plasma drug level 24 h after dose after 12‐week daily dosing with 900 mg/kg/day in rats was 5729 nM. These high doses maintained plasma drug levels well above the K_I values for DPP‐8 and DPP‐9 throughout a 24‐h period. At these high doses, the toxicities of a selective DPP‐8/DPP‐9 inhibitor that were reported previously (100% mortality in mice, alopecia, thrombocytopenia, reticulocytopenia, enlarged lymph nodes, splenomegaly and 20% mortality in rats) were not observed. Conclusions: Inhibition of DPP‐8 and DPP‐9 per se does not lead to organ toxicities and mortality in rodents. Thus, a mechanism other than DPP‐8/DPP‐9 inhibition likely underlies the toxicity previously reported to be associated with a selective DPP‐8/DPP‐9 inhibitor.     

Dipeptidyl‐peptidase IV inhibitor is effective in patients with type 2 diabetes with high serum eicosapentaenoic acid concentrations

Aims/Introduction: Eicosapentaenoic acid (EPA) stimulates glucagon‐like peptide‐1 (GLP‐1) secretion in mice. We investigated the relationship between serum EPA concentrations and the efficacy of dipeptidyl‐peptidase IV (DPP‐4) inhibitor in patients with type 2 diabetes. Materials and Methods: Serum EPA concentrations were measured in 62 consecutive patients with type 2 diabetes who were newly given DPP‐4 inhibitor as a monotherapy or as an add‐on therapy to oral hypoglycemic agents. The dosage of oral hypoglycemic agents was maintained during the observation period. After 24 weeks of treatment with DPP‐4 inhibitor, we evaluated the relationships between a decrease in hemoglobin A1c from baseline and serum EPA concentrations, as well as age, sex, body mass index (BMI), hemoglobin A1c at baseline and usage of antidiabetic concomitant drugs. Results: Hemoglobin A1c was significantly decreased from 8.1 ± 1.1% to 7.2 ± 1.0% by DPP‐4 inhibitor. A decrease in hemoglobin A1c correlated with BMI (r = ?0.396, P = 0.0013), age (r = 0.275, P = 0.0032), hemoglobin A1c at baseline (r = 0.490, P < 0.0001) and log EPA (r = 0.285, P = 0.0246). Multiple regression analysis showed that BMI (β = ?0.419, P = 0.0002), hemoglobin A1c at baseline (β = 0.579, P < 0.0001) and log EPA (β = 0.220, P = 0.0228) were independent determinants of decrease in hemoglobin A1c. Conclusions: DPP‐4 inhibitor is effective in patients with type 2 diabetes with high serum EPA concentrations. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2012.00220.x , 2012)     

Effects of saxagliptin on β-cell stimulation and insulin secretion in patients with type 2 diabetes

Aim: To study the effect of dipeptidyl peptidase‐4 (DPP‐4) inhibition with saxagliptin on β‐cell function as reflected by the stimulated insulin secretion rate after an enteral glucose load in patients with type 2 diabetes. Methods: Patients in this randomized, parallel‐group, double‐blind, placebo‐controlled study were drug‐naÏve, aged 43–69 years, with baseline haemoglobin A1c (HbA1c) 5.9–8.1%. Twenty patients received saxagliptin 5 mg once daily; 16 received placebo. Patients were assessed at baseline and week 12 by intravenous hyperglycaemic clamp (0–180 min, fasting state), and intravenous‐oral hyperglycaemic clamp (180–480 min, postprandial state) following oral ingestion of 75 g glucose. Primary and secondary endpoints were percent changes from baseline in insulin secretion during postprandial and fasting states, respectively. Insulin secretion was calculated by C‐peptide deconvolution. Results: After 12 weeks, saxagliptin significantly increased insulin secretion percent change from baseline during the postprandial state by an 18.5% adjusted difference versus placebo (p = 0.04), an improvement associated with increased peak plasma concentrations of intact glucagon‐like peptide‐1 and glucose‐dependent insulinotropic polypeptide. In the fasting state, saxagliptin significantly increased insulin secretion by a 27.9% adjusted difference versus placebo (p = 0.02). Saxagliptin also improved glucagon area under the curve in the postprandial state (adjusted difference ?21.8% vs. placebo, p = 0.03). Conclusions: DPP‐4 inhibition with saxagliptin improves pancreatic β‐cell function in postprandial and fasting states, and decreases postprandial glucagon concentration. Given the magnitude of enhancement of the insulin response in the fasting state, further study into the effect of DPP‐4 inhibition on the β‐cell is warranted.     

Melatonin attenuates (‐)‐epigallocatehin‐3‐gallate‐triggered hepatotoxicity without compromising its downregulation of hepatic gluconeogenic and lipogenic genes in mice

(‐)‐Epigallocatehin‐3‐gallate (EGCG), a major constituent of green tea, can ameliorate metabolic syndrome at least in part through reducing gluconeogenesis and lipogenesis. Green tea extracts, of which EGCG is a key constituent, have been used for weight loss in humans. A potential adverse effect of high‐dose EGCG or green tea extracts is hepatotoxicity. Melatonin, an endogenous antioxidant with a high safety profile, is effective in preventing various types of tissue damage. The current study investigated the influence of melatonin on EGCG‐triggered hepatotoxicity and EGCG‐downregulated hepatic genes responsible for gluconeogenesis and lipogenesis in mice. We found that (i) melatonin extended survival time of mice intoxicated with lethal doses of EGCG; (ii) melatonin ameliorated acute liver damage and associated hepatic Nrf2 suppression caused by a nonlethal toxic dose of EGCG; (iii) melatonin reduced subacute liver injury and hepatic Nrf2 activation caused by lower toxic doses of EGCG; and (iv) melatonin did not compromise the action of pharmacological doses of EGCG in downregulating a battery of hepatic genes responsible for gluconeogenesis and lipogenesis, including G6Pc, PEPCK, FOXO1α, SCD1, Fasn, leptin, ACCα, ACCβ, GAPT, and Srebp‐1. Taken together, these results suggest that the combination of EGCG and melatonin is an effective approach for preventing potential adverse effects of EGCG as a dietary supplement for metabolic syndrome alleviation and body weight reduction.     

Vildagliptin vs liraglutide as a second‐line therapy switched from sitagliptin‐based regimens in patients with type 2 diabetes: A randomized,parallel‐group study

Introduction

A step-up strategy for dipeptidyl peptidase (DPP)-4 inhibitor-based regimens has not yet been established. In addition, similarities and differences between DPP-4 inhibitors and glucagon-like peptide (GLP)-1 receptor agonists remain to be elucidated in humans. We investigated the pleiotropic effects of vildagliptin vs liraglutide in patients with type 2 diabetes on sitagliptin-based regimens in an open-label, randomized, clinical trial.

Materials and Methods

A total of 122 patients with type 2 diabetes that was inadequately controlled by sitagliptin-based regimens were randomly assigned to either vildagliptin (50 mg, twice daily) or liraglutide treatment (0.9 mg, once daily) for 12 weeks. The primary outcomes were glycated hemoglobin and body mass index.

Results

Both vildagliptin and liraglutide significantly lowered glycated hemoglobin within 12 weeks after switching from sitagliptin, but liraglutide produced a greater reduction (−0.67 ± 0.12% vs −0.36 ± 0.53%). Liraglutide lowered body mass index, whereas vildagliptin did not affect body mass index. Vildagliptin lowered fasting C-peptide immunoreactivity, but liraglutide did not. Vildagliptin increased serum levels of adiponectin, arachidonic acid, eicosapentaenoic acid and docosahexaenoic acid, whereas liraglutide had no effect on these levels. Quality of life, assessed using the diabetes treatment satisfaction questionnaire, was not impaired in either group. The most common adverse events were gastrointestinal symptoms, which occurred with similar frequencies in both groups.

Conclusions

Vildagliptin-mediated improvements in glycemic control did not correlate with indices for insulin secretion and insulin sensitivity. Switching from sitagliptin to liraglutide is useful in managing hyperglycemia and weight. Each agent exerts unique pleiotropic effects. This trial was registered with the University Hospital Medical Information Network Clinical Trials Registry (no. 000004953).     

Efficacy and safety of the dipeptidyl peptidase‐4 inhibitor sitagliptin compared with α‐glucosidase inhibitor in Japanese patients with type 2 diabetes inadequately controlled on sulfonylurea alone (SUCCESS‐2): a multicenter,randomized, open‐label,non‐inferiority trial

We assessed the efficacy and safety of sitagliptin compared with α‐glucosidase inhibitor (αGI) in 120 of Japanese patients with type 2 diabetes mellitus (T2DM) inadequately controlled on stable ≤2 mg/day glimepiride alone [mean hemoglobin A1c (HbA1c) 7.7%] by the randomized, active‐controlled, non‐inferiority trial. Patients were randomly assigned to receive additional sitagliptin or αGI for 24 weeks. The primary endpoint was change in HbA1c from baseline to week 12. After 12 weeks, sitagliptin reduced HbA1c by ?0.44% (p < 0.001) relative to αGI. At 24 weeks, the reduction was almost identical between the groups (?0.091%, p = 0.47). Gastrointestinal disorders were more common with αGI than with sitagliptin, but only minor hypoglycaemia occurred in both groups at similar frequency. These data suggested that sitagliptin was not inferior to αGI for reduction of HbA1c in Japanese T2DM patients receiving glimepiride alone, and well tolerated with minimum risk of gastrointestinal symptoms and hypoglycaemia.     

Cardioprotective effects of dipeptidyl peptidase-4 inhibitors versus sulfonylureas in addition to metformin: A nationwide cohort study of patients with type 2 diabetes

AimsCardiovascular effects of dipeptidyl peptidase-4 inhibitors (DPP4i) versus sulfonylureas (SU) remain controversial in observational studies. This study aimed to evaluate the influence of DPP4i on major adverse cardiovascular events (MACEs), including acute myocardial infarction, cerebrovascular disease, heart failure, cardiogenic shock, malignant dysrhythmia, and revascularisation.Materials and methodsWe conducted a nationwide cohort study using claims data from the National Health Insurance in Taiwan from 2007 to 2013. We enrolled type 2 diabetes patients who received DPP4i or SU in addition to metformin. DPP4i users were matched to SU users using propensity scores at a ratio of 1:1. The study outcomes were hospitalisation for MACE, heart failure, acute myocardial infarction, cerebrovascular disease, coronary revascularisation, and hypoglycaemia.ResultsThere were 37,317 matched pairs of DPP4i and SU users with a mean follow-up of 2.1 years. Compared with SU users, DPP4i users showed a significantly lower risk of hospitalisation for MACE (HR 0.79 [95% CI 0.75-0.82]), heart failure (0.86 [0.79-0.93]), acute myocardial infarction (0.76 [0.68-0.92]), and cerebrovascular disease (0.72 [0.67-0.77]). Both sitagliptin (0.89 [0.85-0.94]) and vildagliptin ([0.77 [0.60-0.99]) showed a significantly lower risk of hospitalisation for MACE, but saxagliptin showed a borderline significantly higher risk of hospitalisation for heart failure (1.59 [1.00-2.55]).ConclusionsDPP4i showed better cardioprotective effects than SU, especially among patients receiving sitagliptin or vildagliptin.     

Bone loss in the oestrogen‐depleted rat is not exacerbated by sitagliptin,either alone or in combination with a thiazolidinedione

Antihyperglycaemic therapy on bone was evaluated in the ovariectomized (OVX), non‐diabetic adult rat. Animals were treated daily for 12 weeks with various doses of sitagliptin, pioglitazone, rosiglitazone, combinations of sitagliptin with pioglitazone or vehicle alone. Sitagliptin target engagement was confirmed by assessing inhibition of plasma dipeptidyl peptidase‐4 (DPP‐4) and oral glucose tolerance. Parameters related to bone health were evaluated in femur and vertebrae by dual‐energy X‐ray absorptiometry and histomorphometry. Bone mineral density (BMD) generally did not differ significantly between OVX‐sitagliptin‐treated animals and OVX‐vehicle controls. In lumbar vertebrae, however, there was significantly less BMD loss with increasing sitagliptin dose. Thiazolidinedione (TZD) treatment generally resulted in lower BMD; OVX‐TZD‐treated (but not OVX‐sitagliptin‐treated) animals also had lessened cortical thickness in central femur and profoundly greater bone marrow adiposity in lumbar vertebrae. These findings support prior findings with TZDs and suggest a neutral or beneficial impact of DPP‐4 inhibition on bone health.     

Effect of single‐dose DPP‐4 inhibitor sitagliptin on β‐cell function and incretin hormone secretion after meal ingestion in healthy volunteers and drug‐naïve,well‐controlled type 2 diabetes subjects

To explore the effects of a single dose of the DPP‐4 inhibitor sitagliptin on glucose‐standardized insulin secretion and β‐cell glucose sensitivity after meal ingestion, 12 healthy and 12 drug‐naïve, well‐controlled type 2 diabetes (T2D) subjects (mean HbA1c 43 mmol/mol, 6.2%) received sitagliptin (100 mg) or placebo before a meal (525 kcal). β‐cell function was measured as the insulin secretory rate at a standardized glucose concentration and the β‐cell glucose sensitivity (the slope between glucose and insulin secretory rate). Incretin levels were also monitored. Sitagliptin increased standardized insulin secretion, in both healthy and T2D subjects, compared to placebo, but without increasing β‐cell glucose sensitivity. Sitagliptin also increased active glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) and reduced total (reflecting the secretion) GIP, but not total GLP‐1 levels. We conclude that a single dose of DPP‐4 inhibition induces dissociated effects on different aspects of β‐cell function and incretin hormones after meal ingestion in both healthy and well‐controlled T2D subjects.     

Effects of vildagliptin on postprandial markers of bone resorption and calcium homeostasis in recently diagnosed, well-controlled type 2 diabetes patients

Background: Bone metabolism is a dynamic process that is influenced by food ingestion. Endogenous incretins have been shown to be important regulators of bone turnover. The aim of the present study was to assess whether a dipeptidylpeptidase (DPP)‐4 inhibitor affects markers of bone resorption and calcium homeostasis. Methods: The present study was a single‐center, double blind, randomized clinical trail. Fifty‐nine drug‐naïve patients with type 2 diabetes (T2D) were randomized to either 1 year treatment with the DPP‐4 inhibitor vildagliptin (100 mg, once daily; n = 29) or placebo (n = 30). Patients received a standardized breakfast after measurement of serum concentrations of cross‐linked C‐terminal telopeptide (s‐CTx), a bone resorption marker influenced by food intake, before and after 50 weeks treatment. Results: Vildagliptin did not change postprandial s‐CTx concentrations compared with pretreatment levels (between‐group ratio 1.15 ± 0.17; P = 0.320). Fasting serum alkaline phosphatase, calcium, and phosphate were also unaffected y 1 year treatment with vildagliptin. Conclusions: Treatment with vildagliptin for 1 year was not associated with changes in markers of bone resorption and calcium homeostasis in drug‐naïve patients with T2D and mild hyperglycemia.     

Clinical results of treating type 2 diabetic patients with sitagliptin, vildagliptin or saxagliptin – diabetes control and potential adverse events

The DPP-4 inhibitors, sitagliptin and vildagliptin, have been shown to improve metabolic control in type 2 diabetes in monotherapy and in combination with metformin, sulphonylurea and thiazolidinediones in studies up to 52 weeks. HbA_1c is reduced by approximately 0.6–1.1%. Similar, albeit more limited, results exist for saxagliptin. DPP-4 inhibitors are safe and tolerable with no increased risk of adverse events compared to placebo and they are associated with only a low risk of hypoglycaemia. The DPP-4 inhibitors are suggested to be used in the early stage of type 2 diabetes, with a main indication in combination with metformin in subjects with inadequate glycaemic control when treated with metformin alone. DPP-4 inhibition may also be used in combination with sulphonylurea and thiazolidinediones. The durability and long-term safety of DPP-4 inhibition remains to be established.     

Running on mixed fuel‐dual agonistic approach of GLP‐1 and GCG receptors leads to beneficial impact on body weight and blood glucose control: A comparative study between mice and non‐human primates

Aim

We performed acute and chronic studies in healthy and diet‐induced obese animals using mouse‐specific or monkey‐specific dual GLP‐1R/GCGR agonists to investigate their effects on food intake, body weight, blood glucose control and insulin secretion. The selective GLP‐1R agonist liraglutide was used as comparator.

Methods

The mouse‐specific dual agonist and liraglutide were tested in lean wild type, GLP‐1R knockout and diet‐induced obese mice at different doses. A chronic study was performed in DIO mice to investigate the effect on body weight, food consumption and total energy expenditure (TEE) in obese and diabetic monkeys with a focus on body weight and energy intake.

Results

The mouse‐specific dual agonist and liraglutide similarly affected glycaemic control. A higher loss in body weight was measured in dual agonist‐treated obese mice. The dual agonist significantly enhanced plasma glucose excursion in overnight fed GLP‐1R^?/? mice, probably reflecting a potent GCGR agonist activity. It increased TEE and enhanced fat and carbohydrate oxidation, while liraglutide produced no effect on TEE. In obese and diabetic monkeys, treatment with the monkey‐specific dual agonist reduced total energy intake to 60%‐70% of baseline TEI during chronic treatment. A decrease in body weight and significant improvement in glucose tolerance was observed.

Conclusions

In DIO mice and non‐human primates, dual agonists elicited robust glycaemic control, similar to the marketed GLP‐1R agonist, while eliciting greater effects on body weight. Results from DIO mice suggest that the increase in TEE is caused not only by increased fat oxidation but also by an increase in carbohydrate oxidation.     

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

Aim: Alogliptin, a dipeptidyl peptidase‐4 (DPP‐4) inhibitor, and voglibose, an alpha‐glucosidase inhibitor, have different but complementary mechanisms of action on glucagon‐like peptide‐1 (GLP‐1) regulation and glucose‐lowering effects. The present study evaluated the chronic effects of combination treatment with alogliptin and voglibose in prediabetic db/db mice. Methods: Alogliptin (0.03%) and voglibose (0.001%) alone or in combination were administered in the diet to prediabetic db/db mice. Results: After 3 weeks, voglibose treatment increased GLP‐1 secretion (voglibose alone, 1.6‐fold; alogliptin plus voglibose, 1.5‐fold), while it decreased plasma glucose‐dependent insulinotropic polypeptide (GIP) (voglibose alone, ?30%; alogliptin plus voglibose, ?29%). Alogliptin, voglibose and combination treatment decreased plasma DPP‐4 activity by 72, 15 and additively by 80%, respectively, and increased plasma active GLP‐1 levels by 4.5‐, 1.8‐ and synergistically by 9.1‐fold respectively. Combination treatment increased plasma insulin by 3.6‐fold (alogliptin alone, 1.3‐fold; voglibose alone, 1.8‐fold), decreased plasma glucagon by 30% (alogliptin alone, 11%; voglibose alone, 8%), and prevented the development of diabetes, much more effectively than either agent alone. After 4 weeks, alogliptin, voglibose and combination treatment increased pancreatic insulin content by 1.6‐, 3.4‐ and synergistically by 8.5‐fold respectively. Furthermore, combination treatment resulted in an increased expression of insulin, pancreatic and duodenal homeobox 1 (PDX1) and glucose transporter 2 (GLUT2), and maintenance of normal beta/alpha‐cell distribution in the pancreatic islet. Conclusions: Chronic treatment with alogliptin in combination with voglibose concurrently increased active GLP‐1 circulation, increased insulin secretion, decreased glucagon secretion, prevented the onset of the disease, and preserved pancreatic beta‐cells and islet structure in prediabetic db/db mice.     

Oral therapy for type 1 diabetes mellitus using a novel immunomodulator,FTY720 (fingolimod), in combination with sitagliptin,a dipeptidyl peptidase‐4 inhibitor,examined in non‐obese diabetic mice

Aims/Introduction: The therapeutic effectiveness against type 1 diabetes mellitus of a novel immunomodulator, FTY720 (fingolimod), in combination with sitagliptin, a dipeptidyl peptidase‐4 inhibitor, was examined in the non‐obese diabetic (NOD) mouse model. Materials and Methods: Female NOD mice that had developed type 1 diabetes mellitus spontaneously were divided into four groups according to which therapy they received: (i) FTY720 (0.1 mg/kg, orally, six times a week) plus sitagliptin (1 mg/kg, orally, six times a week); (ii) FTY720 (0.1 mg/kg, orally, six times a week); (iii) sitagliptin (1 mg/kg, orally, six times a week); and (iv) the vehicle (water) alone. Therapeutic efficacy was evaluated in terms of survival rate, ratio of insulin‐positive β‐cells/total islet area, extent of islet inflammation (insulitis score) and blood‐glucose level. Results: The therapeutic administration of FTY720 plus sitagliptin significantly improved survival (83% at 70 days after onset, P < 0.05) compared with sitagliptin alone (17%) or vehicle alone (0%). The fasting‐blood glucose level, the ratio of insulin‐positive β‐cells/total islet area and the insulitis score in the surviving mice, which had been treated with FTY720 plus sitagliptin, were improved to the normal levels as in age‐matched NOD mice with normoglycemia. Conclusions: Combination therapy with FTY720 and sitagliptin is a promising candidate for type 1 diabetes mellitus treatment, and might allow the treatment of type 1 diabetes mellitus with only oral agents. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2012.00218.x , 2012)     

Analysis of N1‐acetyl‐N2‐formyl‐5‐methoxykynuramine/N1‐acetyl‐5‐methoxy‐kynuramine formation from melatonin in mice

Abstract: The interactions of melatonin, a potent endogenous antioxidant, with reactive oxygen species generate several products that include N¹‐acetyl‐N²‐formyl‐5‐methoxykynuramine (AFMK) and N¹‐acetyl‐5‐methoxy‐kynuramine (AMK). The physiological or pathological significance of AFMK/AMK formation during the process of melatonin metabolism in mammals has not been clarified. Using a metabolomic approach in the current study, the AFMK/AMK pathway was thoroughly investigated both in mice and humans. Unexpectedly, AFMK and AMK were not identified in the urine of humans nor in the urine, feces or tissues (including liver, brain, and eyes) in mice under the current experimental conditions. Metabolomic analysis did identify novel metabolites of AMK, i.e. hydroxy‐AMK and glucuronide‐conjugated hydroxy‐AMK. These two newly identified metabolites were, however, not found in the urine of humans. In addition, oxidative stress induced by acetaminophen in the mouse model did not boost AFMK/AMK formation. These data suggest that AFMK/AMK formation is not a significant pathway of melatonin disposition in mice, even under conditions of oxidative stress.