Alogliptin: a DPP-4 inhibitor modulating adipose tissue insulin resistance and atherogenic lipid.

AIMS: The purpose of this study is to investigate the regulation of adipose tissue insulin resistance with DPP-4 inhibitors in treatment-naive subjects with T2DM and to examine its relation to other diabetic parameters. SUBJECTS AND METHODS: A total of 147 subjects were treated with alogliptin 12.5-25 mg/day (n = 55), sitagliptin 25-50 mg/day (n = 49), or teneligliptin 10-20 mg/day (n = 43) monotherapy for 3 months. Changes in adipo-IR, a mathematical model used to evaluate adipose tissue insulin resistance, and various diabetic parameters were analyzed in this prospective, non-randomized observational study. RESULTS: Among these three drugs, only alogliptin significantly reduced adipo-IR (-25.9%, p < 0.004) and some lipid parameters, such as LDL-C, T-C/HDL-C, log(TG)/HDL-C, non-HDL-C/HDL-C, and LDL-C/HDL-C. Subjects in the alogliptin group were divided into two groups with distinct changes in adipo-IR. Group A had a significant decrease in adipo-IR (-56.5%, p < 0.00001, n = 28), whereas group B had an insignificant increase (19.1%, p = 0.055, n = 27). Significant reductions in FBG or HbA1c were observed in groups A and B, respectively. Group A also showed significant reductions in HOMA-R, T-C/HDL-C, TG, log(TG)/HDL-C, non-HDL-C/HDL-C, LDL-C/HDL-C, and FFA, as well as increases in QUICKI or HDL-C. In contrast, group B showed significant reductions in QUICKI or LDL-C, and increases in HOMA-R, insulin, HOMA-B, C-peptide, or CPR-index. CONCLUSIONS: In contrast to other tested DPP-4 inhibitors, alogliptin demonstrated the ability to down-regulate insulin resistance in adipose tissue, as well as certain atherogenic lipids. This study provides the initial evidence of a DPP-4 inhibitor's potential to regulate adipose tissue insulin resistance. Furthermore, adipo-IR is associated with non-LDL-C lipid parameters instead of glycemic control in those receiving alogliptin.

Protective effect of alogliptin against cyclophosphamide-induced lung toxicity in rats: Impact on PI3K/Akt/FoxO1 pathway and downstream inflammatory cascades.

Cyclophosphamide (CP)-induced lung toxicity is a remaining obstacle against the beneficial use of this chemotherapeutic agent. More considerations were given to the role of Alogliptin (ALO) in ameliorating CP-induced toxicities in many tissues. We designed this study to clarify the protective potential of ALO against CP-induced lung toxicity in rats. ALO was administered for 7 days. Single-dose CP was injected on the 2nd day (200 mg/kg: i.p.) to induce lung toxicity. Rats were divided into four groups: control, ALO-treated, CP-treated and ALO + CP-treated group. Leucocytic count, total proteins, LDH activity, TNF-α, and IL-6 were estimated in the bronchoalveolar lavage fluid (BALF). The oxidative/antioxidants (MDA, Nrf2, TAO and GSH), inflammatory (NFκB), fibrotic (TGF-ß1) and apoptotic (PI3K/Akt/FoxO1) markers in pulmonary homogenates were biochemically evaluated. Rat lung sections were examined histologically (light and electron microscopic examination) and immunohistochemically (for iNOS and CD68 positive alveolar macrophages). CP significantly increased oxidative stress, inflammation, fibrosis, and apoptosis markers as well as deteriorated the histopathological pulmonary architecture. These hazardous effects were significantly ameliorated by ALO treatment. ALO protected against CP-induced lung toxicity by mitigating the oxidative, inflammatory and fibrotic impacts making it a promising pharmacological therapy for mitigating CP-induced lung toxicity.

Hantzsch condensation reaction as a spectrofluorometric method for determination of alogliptin, an antidiabetic drug, in pure form, tablet form, and human and rat plasma.

To analyze alogliptin in its pharmaceutical dosage forms and human plasma, a sensitive, inexpensive, simple, and precise spectrofluorimetric method was developed and tested. This method was also used to investigate the drug's pharmacokinetic behaviour in the blood of rats. This was based on the Hantzsch reaction, which produces yellowish luminous products that can be detected spectrofluorometrically at 480 and 415 nm for emission and excitation, respectively, when the primary amine group in the examined drug reacts with acetylacetone and formaldehyde. Several experimental parameters that affect the reaction product's development and stability were explored and improved. The curve of fluorescence and concentration for alogliptin was linear in the concentration range 0.05-3.60 µg ml-1 . The proposed approach was validated according to International Council for Harmonization criteria. The method was successfully utilized to evaluate the examined drug in dose formulations and spiked human plasma with high accuracy.

Alogliptin attenuates cyclophosphamide-induced nephrotoxicity: a novel therapeutic approach through modulating MAP3K/JNK/SMAD3 signaling cascade.

Cyclophosphamide (CP) is widely used as a chemotherapy against various types of cancers. However, CP is accompanied with multiple organ toxicity due to production of reactive oxygen species (ROS), induction of inflammation and consequently apoptosis. Alogliptin (Alo) is a dipeptidyl peptidase 4 (DPP-IV) inhibitor, which is booming as an antidiabetic agent. Interestingly, gliptins are currently studied for their counter-regulatory effects against oxidative stress and inflammation via multiple pathways, among which is the mitogen-activated protein kinase (MAPK)/c-Jun N-terminal kinase (JNK) pathway. This cascade can reduce inflammation via mitigating the activity of mothers against decapentaplegic homolog 3 (SMAD3) and c-Jun. However, Alo effect against CP-induced kidney injury has not been previously elucidated. This tempted us to investigate the possible beneficial effect of Alo against CP-induced kidney injury via modulating the MAP3K/JNK/SMAD3 signaling cascade. Thirty-two male Wistar rats were randomly allocated into four groups. CP-treated group received a single dose of CP (200 mg/kg; i.p.). Alo-treated group received Alo (20 mg/kg/day; p.o.) for 7 days with single CP injection on day 2. Marked decrease in renal injury was observed upon Alo treatment, as evidenced through declined serum kidney function markers, oxidative stress and apoptosis markers, MAP3K expression, phospho (p)-SMAD3, p-JNK, and p-c-Jun levels. These cellular effects were reflected in reduced transforming growth factor beta (TGF-ß) and tumor necrosis factor alpha (TNF-α) fibrotic and inflammatory mediators, coinciding with improved histopathological portrait. In conclusion, the current study provides novel application of Alo as a therapeutic modality against CP-induced nephrotoxicity.

Formulation and Optimization of Alogliptin-Loaded Polymeric Nanoparticles: In Vitro to In Vivo Assessment.

The nano-drug delivery system has gained greater acceptability for poorly soluble drugs. Alogliptin (ALG) is a FDA-approved oral anti-hyperglycemic drug that inhibits dipeptidyl peptidase-4. The present study is designed to prepare polymeric ALG nanoparticles (NPs) for the management of diabetes. ALG-NPs were prepared using the nanoprecipitation method and further optimized by Box−Behnken experimental design (BBD). The formulation was optimized by varying the independent variables Eudragit RSPO (A), Tween 20 (B), and sonication time (C), and the effects on the hydrodynamic diameter (Y1) and entrapment efficiency (Y2) were evaluated. The optimized ALG-NPs were further evaluated for in vitro release, intestinal permeation, and pharmacokinetic and anti-diabetic activity. The prepared ALG-NPs show a hydrodynamic diameter of between 272.34 nm and 482.87 nm, and an entrapment efficiency of between 64.43 and 95.21%. The in vitro release data of ALG-NPs reveals a prolonged release pattern (84.52 ± 4.1%) in 24 h. The permeation study results show a 2.35-fold higher permeation flux than pure ALG. ALG-NPs exhibit a significantly (p < 0.05) higher pharmacokinetic profile than pure ALG. They also significantly (p < 0.05) reduce the blood sugar levels as compared to pure ALG. The findings of the study support the application of ALG-entrapped Eudragit RSPO nanoparticles as an alternative carrier for the improvement of therapeutic activity.

Alogliptin Attenuates Lipopolysaccharide-Induced Neuroinflammation in Mice Through Modulation of TLR4/MYD88/NF-κB and miRNA-155/SOCS-1 Signaling Pathways.

BACKGROUND: Endotoxin-induced neuroinflammation plays a crucial role in the pathogenesis and progression of various neurodegenerative diseases. A growing body of evidence supports that incretin-acting drugs possess various neuroprotective effects that can improve learning and memory impairments in Alzheimer's disease models. Thus, the present study aimed to investigate whether alogliptin, a dipeptidyl peptidase-4 inhibitor, has neuroprotective effects against lipopolysaccharide (LPS)-induced neuroinflammation and cognitive impairment in mice as well as the potential mechanisms underlying these effects. METHODS: Mice were treated with alogliptin (20 mg/kg/d; p.o.) for 14 days, starting 1 day prior to intracerebroventricular LPS injection (8 µg/µL in 3 µL). RESULTS: Alogliptin treatment alleviated LPS-induced cognitive impairment as assessed by Morris water maze and novel object recognition tests. Moreover, alogliptin reversed LPS-induced increases in toll-like receptor 4 and myeloid differentiation primary response 88 protein expression, nuclear factor-κB p65 content, and microRNA-155 gene expression. It also rescued LPS-induced decreases in suppressor of cytokine signaling gene expression, cyclic adenosine monophosphate (cAMP) content, and phosphorylated cAMP response element binding protein expression in the brain. CONCLUSION: The present study sheds light on the potential neuroprotective effects of alogliptin against intracerebroventricular LPS-induced neuroinflammation and its associated memory impairment via inhibition of toll-like receptor 4/ myeloid differentiation primary response 88/ nuclear factor-κB signaling, modulation of microRNA-155/suppressor of cytokine signaling-1 expression, and enhancement of cAMP/phosphorylated cAMP response element binding protein signaling.

Red cell distribution width in patients with diabetes and myocardial infarction: An analysis from the EXAMINE trial.

AIM: To determine the clinical correlates of increased red blood cell distribution width (RDW), its potential mechanistic association with multiple circulating biomarkers, and its prognostic value in patients with type 2 diabetes (T2D) who had a recent acute coronary syndrome. METHODS: We used time-updated Cox models applied to patients enrolled in the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) trial. RESULTS: A total of 5380 patients were included, the median age was 61 years and 32% were women. Patients with higher RDW were older, more frequently women, with a longer diabetes duration and increased co-morbidities. An RDW of more than 16.1% (both baseline and time-updated) was independently associated with the study primary composite outcome of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death (time-updated adjusted HR = 1.36, 95% CI = 1.16-1.61, p < .001), all-cause death (time-updated adjusted HR = 2.01, 95% CI = 1.60-2.53, p < .001), as well as mortality from non-cardiovascular causes (time-updated adjusted HR = 2.67, 95% CI = 1.72-4.15, p < .001). RDW had a weak-to-moderate correlation with haemoglobin and circulating markers that reflected inflammation, apoptosis, fibrosis and congestion. Alogliptin did not alter RDW values. CONCLUSIONS: RDW is a marker of disease severity associated with a multitude of poor outcomes, including both cardiovascular and non-cardiovascular death. RDW correlated modestly with inflammatory, pro-apoptotic, pro-fibrotic and congestion markers, and its levels were not affected by alogliptin during the course of the trial.

Intestinal Absorption of Alogliptin Is Mediated by a Fruit-Juice-Sensitive Transporter.

Alogliptin (ALG), an inhibitor of dipeptidylpeptidase-4, is used in the management of type 2 diabetes mellitus, and has a high absorption rate (>60-71%), despite its low lipophilicity (logP=-1.4). Here, we aimed to clarify the mechanism of its intestinal absorption. ALG uptake into Caco-2 cells was time-, temperature-, and concentration-dependent, but was not saturated at concentrations up to 10 mmol/L. The uptake was significantly inhibited by the organic anion transporting polypeptide (OATP) substrate fexofenadine and by the OATP inhibitor 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), but was not inhibited by organic cation transporter (OCT)/organic cation/carnitine transporter (OCTN) or peptide transporter 1 (PEPT1) substrates. Grapefruit, orange, and apple juices and their constituents, which are known to strongly inhibit intestinal OATPs, significantly inhibited ALG uptake into Caco-2 cells. The pH dependence was bell-shaped, indicating the involvement of a pH-sensitive transporter. However, ALG uptake by HEK293 cells overexpressing OATP2B1, a key intestinal OATP transporter of amphiphilic drugs, was not different from that of mock cells. In a rat in vivo study, apple juice reduced systemic exposure to orally administered ALG without changing the terminal half-life. These observations suggest that intestinal absorption of ALG is carrier-mediated, and involves a fruit-juice-sensitive transporter other than OATP2B1.

Different chromatographic methods for determination of alogliptin benzoate, metformin hydrochloride, and metformin impurity in bulk and pharmaceutical dosage form.

Two simple, sensitive, and reproducible methods were developed for the determination of alogliptin and metformin hydrochloride in presence of metformin impurity "melamin" in pure form and in pharmaceutical formulation. Method (A) was a thin layer chromatographic method in which separation was achieved using ethyl acetate-methanol-formic acid (6:3.8:0.2, by volume) as a developing system followed by densitometric scanning at 230 nm. Method (B) was a high-performance liquid chromatography method; separation was achieved on C18 column, the mobile phase consisted of a mixture of sodium lauryl sulfate buffer 0.1% w/v, pH 3: methanol in the ratio 70:30, v/v and measurement was done at 220 nm. System suitability testing parameters were calculated to ascertain the quality performance of the developed chromatographic methods. The proposed methods have been validated regarding accuracy, precision, and selectivity, moreover they have been successfully applied to Westirizide tablets containing both alogliptin and metformin hydrochloride, results indicate that there was no interference from additives. No significance difference was found when these methods were compared to the reported one.

Alogliptin after acute coronary syndrome in patients with type 2 diabetes: a renal function stratified analysis of the EXAMINE trial.

BACKGROUND: The EXAMINE trial tested the efficacy and safety of alogliptin, an inhibitor of dipeptidyl peptidase 4, compared with placebo in 5380 patients with type 2 diabetes and a recent acute coronary syndrome. Because alogliptin is cleared by the kidney, patients were stratified according to screening renal function within two independently randomized strata: (1) estimated glomerular filtration rate (eGFR) ≥ 60 ml/min/1.73m2 and (2) eGFR < 60 ml/min/1.73m2. We aim to assess the efficacy and safety of alogliptin vs. placebo according to the renal function strata. METHODS: Cox-proportional hazard models with an interaction term by renal function strata were used. The primary endpoint was a composite of cardiovascular death, nonfatal myocardial infarction (MI), or nonfatal stroke. RESULTS: Patient characteristics were balanced within each renal function strata. In total, 3946 patients were randomized within the eGFR ≥ 60 stratum, and 1434 patients within the eGFR < 60 stratum. The effect of alogliptin was modified by the renal function strata. PRIMARY OUTCOME: eGFR ≥ 60 HR = 0.81, 95%CI, 0.65-0.99, and eGFR < 60 HR = 1.20, 95%CI, 0.95-1.53; interactionp = 0.014. Cardiovascular death: eGFR ≥ 60 HR = 0.61, 95%CI, 0.42-0.88, and eGFR < 60 HR = 1.16, 95%CI, 0.82-1.65; interactionp = 0.013. Non-fatal MI: eGFR ≥ 60 HR = 0.86, 95%CI, 0.66-1.13, and eGFR < 60 HR = 1.48, 95%CI, 1.07-2.06; interactionp = 0.013. CONCLUSIONS: Alogliptin may benefit patients with eGFR ≥ 60, but may be detrimental to patients with eGFR < 60 ml/min/1.73m2. These hypothesis-generating findings require further validation to assess the potential benefit and risk of alogliptin across the renal function spectrum among patients with type 2 diabetes and a recent acute coronary syndrome. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00968708.

Antiproteinuric effect of DPP-IV inhibitors in diabetic and non-diabetic kidney diseases.

Diabetes Mellitus (DM) is a chronic and severe metabolic disease, characterized by chronic hyperglycemia due to insulin resistance and/or reduced insulin secretion. Concerning the non-insulin glucose-lowering therapy for diabetes, Dipeptidyl-peptidase-4 (DPP-4) inhibitors, members of the incretin family, represent new agents, capable of a glycemic control improvement with an advantageous safety profile, given the absence of weight gain, the low incidence of hypoglycemia and the good renal tolerance in patients suffering from chronic renal failure. In addition to demonstrating efficacy in glycemic control through inhibition of GLP-1 degradation, DPP-4 inhibitors (DPP-4is) seem to demonstrate pleiotropic effects, which also make them interesting in both diabetic and non-diabetic nephropathies, especially for their capacity of reducing proteinuria. Several studies about diabetic nephropathy on patients' cohorts and murine models have demonstrated a solid direct relationship between DPP-4 activity and urinary albumin excretion (UAE), thus confirming the capacity of DPP-4is to reduce proteinuria; the mechanism responsible for that effect was studied to assess if it was the result of a direct action on renal impairment or a secondary consequence of the better glycemic control related to these agents. As a result of these more in-depth studies, DPP-4is have demonstrated an improvement of renal inflammation markers and consequent proteinuria reduction, regardless of glucose concentrations. Considering the nephroprotective effects of DPP-4is might be glycemic independent, several studies were conducted to prove the validity of the same effects in non-diabetic nephropathies. Among these studies, DPP-4is demonstrated an improvement of various renal inflammatory markers on several models of non-diabetes dependent renal impairment, confirming their capacity to reduce proteinuria, independently from the action on glucose metabolism. The objective of this review is to present and discuss the so far demonstrated antiproteinuric effect of DPP-4is and their effects on diabetic and non-diabetic nephropathies.

Novel spectrofluorimetric quantification of alogliptin benzoate in biofluids exploiting its interaction with 4-chloro-7-nitrobenzofurazan.

The direct determination of alogliptin benzoate (ALO) using fluorescence has not yet been accomplished because ALO cannot fluoresce naturally. Accordingly, it should be derivatized first with a fluorogenic reagent to enhance the sensitivity required for its bioanalysis. This method is the first spectrofluorimetric assay for ALO quantification exploiting the nucleophilic nature of its amino group to react with 4-chloro-7-nitrobenzofurazan (NBD-Cl) in borate buffer at pH 8.5 to produce a strong fluorescent compound that is excited at and emits at wavelengths 470 and 527 nm, respectively. Experimental variables concerning the conditions of reaction and fluorogenic intensity were carefully investigated and optimized. Linearity was from 1-250 ng ml-1 with a lower detection limit of 0.29 ng ml-1 and a lower quantification limit of 0.88 ng ml-1 . Validation of the current study was accomplished with mean per cent recovery of 100.62 ± 1.59 in tablets and 99.86 ± 0.82 in human plasma. Furthermore, the current method has been utilized in the bioanalysis of ALO in real rat plasma after oral administration with a simple specimen preparation. The developed method has proven to be a promising alternative method for ALO analysis in bioequivalence studies.

Alogliptin alleviates liver fibrosis via suppression of activated hepatic stellate cell.

Liver fibrosis occurs in most types of chronic liver diseases. The understanding of the pathogenesis of liver fibrosis has grown considerably, but the effective treatments are still lacking. Alogliptin, a classical Dipeptidyl peptidase-4 (DPP4) inhibitor with great effects on type 2 diabetes, has shown the potential to protect liver, but its effects on the progression of liver fibrosis have not been clarified. Herein, we explored the anti-fibrosis effects of alogliptin. In vitro, we demonstrated that alogliptin suppressed the activation of LX-2 upon transforming growth factor-ß (TGF-ß) challenge. In vivo, chronic treatment with alogliptin alleviated hepatic steatosis and protected from the liver injury in ob/ob mice, which delayed the progression of liver fibrosis. Furthermore, alogliptin significantly relieved the hepatic fibrosis in CCl4-induced liver fibrosis mouse model. In conclusion, our results demonstrate that negatively modulation of alogliptin on hepatic stellate cell (HSC) activation might contribute to liver fibrosis alleviation. Our research provides the potential possibility of alogliptin on the application for liver fibrosis therapy and suggests that DPP4 may be a novel target for liver fibrosis therapy.

Cardiovascular protection in type 2 diabetes: Insights from recent outcome trials.

This review examines recent randomized controlled cardiovascular (CV) outcome trials of glucose-lowering therapies in type 2 diabetes and their impact on the treatment of patients with type 2 diabetes. The trials were designed to comply with regulatory requirements to confirm that major adverse cardiac events (MACE) are not detrimentally affected by such therapies. Trials involving dipeptidyl peptidase-4 (DPP-4) inhibitors did not alter a composite MACE outcome comprising CV deaths, non-fatal myocardial infarction and non-fatal stroke; however, the possibility that some members of this class might incur a small increased risk or worsening of heart failure cannot be excluded. Some studies on glucagon-like peptide-1 receptor agonists (liraglutide: LEADER trial; semaglutide: SUSTAIN-6 trial) found significant benefits for MACE, while treatment with sodium-glucose co-transporter-2 inhibitors (empagliflozin: EMPA-REG OUTCOME trial; canagliflozin: CANVAS trial) also significantly reduced MACE and reduced hospitalization for heart failure. Comparisons among trials are complicated by variance in the populations recruited, particularly CV status at randomization, and differences in trial design, data collection and analyses. A large proportion of patients recruited into these trials have previously experienced adverse CV events; thus, the therapies are mostly assessing secondary prevention of a further event. This contrasts with the overall type 2 diabetes population receiving glucose-lowering therapies, of whom the majority will not have had MACE and will be regarded as primary prevention. Overall, the trials provide reassuring evidence that new glucose-lowering medications do not adversely affect CV events and some of these agents may offer CV protection.

Type 2 diabetes and the kidney: Insights from cardiovascular outcome trials.

Diabetic kidney disease (DKD) still remains a progressive condition that is associated with higher risk of end-stage kidney disease and significant cardiovascular morbidity and mortality. Twelve cardiovascular outcome trials in type 2 diabetes (T2D) have been published to date. Most trials with dipeptidyl-peptidase inhibitors (SAVOR-TIMI 53 with saxagliptin, EXAMINE with alogliptin, TECOS with sitagliptin, and CARMELINA with linagliptin) and with glucagon-like peptide-1 receptor agonists (GLP-1RAs) (ELIXA with lixisenatide, LEADER with liraglutide, SUSTAIN-6 with semaglutide, EXCSEL with exenatide once-weekly, and HARMONY with albiglutide) pointed towards reduced albuminuria, which is a surrogate endpoint possibly heralding renal function preservation. The three trials with sodium-glucose co-transporter-2 inhibitors (SGLT-2is) (empagliflozin, canagliflozin and dapagliflozin) also showed a salutary effect on long-term estimated glomerular filtration rate, suggesting that SGLT-2is are more effective at mitigating loss of kidney function than incretin-based therapies; moreover, SGLT-2is also have the advantage of plausible haemodynamic mechanisms for improved renal outcomes. Despite some residual limitations linked to differences in study populations and patient characteristics, the cardiorenal protective actions of SGLT-2is, and to a lesser extent some GLP-1RAs, make them favourable medications for patients with T2D at increased cardiorenal risk. There is room for optimism that their use may change the paradigm of the ineluctable progression of DKD.

Heart failure and type 2 diabetes: From cardiovascular outcome trials, with hope.

An excess risk of heart failure (HF) persists in patients with type 2 diabetes (T2D) despite optimal control of an array of conventional risk factors, including hyperglycaemia. Twelve cardiovascular outcome trials (CVOTs) have been published to date, although none, with the exception of the DECLARE trial with dapagliflozin, has included HF as a primary endpoint. The four trials with dipeptidyl-peptidase inhibitors (DPP-4i) (SAVOR-TIMI 53 with saxagliptin, EXAMINE with alogliptin, TECOS with sitagliptin and CARMELINA with linagliptin) failed to show any significant effect on HF risk in patients with T2D, with the notable exception of saxagliptin which was associated with a 27% increased risk. Five completed CVOTs with the GLP-1 RAs lixisenatide (ELIXA), liraglutide (LEADER), semaglutide (SUSTAIN-6), exenatide once weekly (EXSCEL) and albiglutide (HARMONY) also failed to reveal any significant effect on HF risk. The three trials with sodium glucose co-transporter-2 inhibitors (SGLT-2i) (EMPA-REG OUTCOME with empagliflozin, CANVAS with canagliflozin and DECLARE with dapagliflozin) all revealed a robust and significant reduction in the hazard ratios of hospitalization for HF, from 27% to 35%, which remained consistent, significant and of similar magnitude regardless of the presence of a history of HF or established atherosclerotic cardiovascular disease. There is no association between reductions in HF risk and haemoglobin A1c (A1C) levels, while there is a significant association between reductions in HR for MACE and A1C levels (Spearman's correlation, r = 0.695; P = 0.013). All of the 12 CVOTs completed to date have provided reassurance of the overall cardiovascular safety of the newer anti-hyperglycaemic drugs. At present, the robust, consistent and reproducible reduction of approximately 30% in the risk of HF with SGLT-2i may be considered a class effect. The beneficial effect on MACE outcome observed with the use of some GLP-1RAs and SGLT-2i must be interpreted within the frame of the single trial.

Different daily glycemic profiles after switching from once-daily alogliptin plus twice-daily metformin to their once-daily fixed-dose combination in Japanese type 2 diabetic patients.

The aim of this study was to investigate whether daily glycemic profiles and treatment satisfaction would be changed after switching from once-daily 25-mg alogliptin plus twice-daily 250-mg metformin to the fixed-dose combination of 25-mg alogliptin and 500-mg metformin once daily in type 2 diabetic patients. Twenty adult Japanese type 2 diabetic patients in whom once-daily 25-mg alogliptin plus twice-daily 250-mg metformin were switched to the fixed-dose combination of 25-mg alogliptin and 500-mg metformin once daily participated. Before and one month after the switch, participants were asked to perform one day of seven-point self-monitoring of blood glucose (SMBG), to wear a sensor of flash glucose monitoring for up to 14 days, and to respond to a questionnaire for treatment satisfaction. As a result, the SMBG profiles were significantly changed after the switch (p = 0.021); blood glucose levels 2 hours after breakfast were significantly elevated (p = 0.022), whereas those 2 hours after lunch were significantly reduced (p = 0.036). The flash glucose monitoring also demonstrated a significant change of daily glucose profiles (p < 0.001). The risk of glucose levels <80 mg/dL were decreased from evening to morning, while the risk of glucose levels ≥140 mg/dL were increased. Mean 24-hour glucose values were increased by 5 mg/dL on average (p < 0.001). Treatment satisfaction was significantly improved after the switch (p < 0.001). In conclusion, daily glycemic profiles were significantly changed after switching from once-daily 25-mg alogliptin plus twice-daily 250-mg metformin to the once-daily fixed-dose combination in Japanese type 2 diabetic patients. Treatment satisfaction was significantly improved after the switch.

Combination effects of alogliptin and pioglitazone on steatosis and hepatic fibrosis formation in a mouse model of non-alcoholic steatohepatitis.

This study aimed to evaluate the effects of combination therapy with a dipeptidyl peptidase-4 inhibitor, alogliptin, and a peroxisome proliferator-activated receptor-γ agonist, pioglitazone, in a preclinical model of nonalcoholic steatohepatitis using low-density lipoprotein receptor-knockout mice fed a modified choline-deficient l-amino acid-defined diet. Monotherapy with either alogliptin (10-200 mg/kg) or pioglitazone (6-20 mg/kg) significantly decreased hepatic triglyceride content and fibrosis. The concomitant treatment of alogliptin (30 mg/kg), pioglitazone (20 mg/kg) also decreased hepatic triglyceride and hepatic collagen-I mRNA at greater extent compared to monotherapy. Hepatic expression of CD11b mRNA and monocyte chemoattractant protein-1 were also reduced by the concomitant treatment. These results suggest that via an anti-inflammatory potential in addition to anti-metabolic effects, the combination therapy of alogliptin and pioglitazone may provide therapeutic benefits to type 2 diabetes patients with nonalcoholic steatohepatitis, which will be proven in controlled clinical trials.

Exploring the effects of DPP-4 inhibitors on the kidney from the bench to clinical trials.

Dipeptidyl-peptidase-4 (DPP-4) inhibitors are a relatively new class of non-insulin glucose-lowering agents, belonging to the incretin family, which are able to improve glycemic control with a favorable safety profile, since they are associated with a low risk of hypoglycemia, no weight gain, and good tolerability in patients with chronic renal failure. Some experimental and clinical studies suggest that these drugs may exert significant pleiotropic effects, in particular on chronic kidney disease (CKD) progression, but data from clinical trials are still controversial. In an effort to clarify the effects of DPP-4 inhibitors (DPP-4is) on diabetes-related renal damage, we performed a narrative review of available clinical trials and other experimental studies focusing on renal effects of DPP-4is. Currently, there is no conclusive evidence proving the usefulness of this drug class for improving diabetes-related renal damage. However, our literature review suggests that DPP-4is are safe and well tolerated in type 2 diabetes mellitus (T2DM) patients with CKD. More importantly, results from the reviewed studies indicate that DPP-4 inhibitor therapy may improve two major risk factors for diabetic nephropathy, such as hyperglycemia and albuminuria, resulting in potential renal benefits beyond glycemic control. Despite several limitations, the conclusions of our review corroborate previous evidence on the potential renal benefits of DPP-4is, highlighting the urgent need of future trials adequately powered and designed on hard renal outcomes to ascertain (or contradict) the therapeutic benefit of DPP-4is in T2DM and CKD patients.

A high-performance liquid chromatography-tandem mass spectrometry method for simultaneous determination of imigliptin, its five metabolites and alogliptin in human plasma and urine and its application to a multiple-dose pharmacokinetic study.

Imigliptin is a novel DPP-4 inhibitor, designed to treat type 2 diabetes mellitus (T2DM). A selective and sensitive method was developed using high performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS) to simultaneously quantify imigliptin, its five metabolites, and alogliptin in human plasma and urine. Solid-phase extraction (SPE) and direct dilution were used to extract imigliptin, its five metabolites, alogliptin from plasma and urine, respectively. The extracts were injected onto a SymmetryShield RP8 column with a gradient elution of methanol and water containing 10 mM ammonium formate (pH = 7). Ionization of all analytes was performed using an electrospray ionization (ESI) source in positive mode and detection was carried out with multiple reaction monitoring (MRM) mode. The results revealed that the method had excellent selectivity and linearity. Inter- and intra-batch precisions of all analytes were less than 15% and the accuracies were within 85%-115% for both plasma and urine. The sensitivity, matrix effect, extraction recovery, linearity, and stabilities were validated for all analytes in human plasma and urine. In conclusion, the validation results showed that this method was robust, specific, and sensitive and it can successfully applied to a pharmacokinetic study of Chinese T2DM subjects after oral dose of imigliptin and alogliptin.