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Background: We evaluated the effect of a dipeptidyl peptidase‐4 inhibitor (DPP‐4i) on the progression of obstructive coronary artery disease (OCAD) in patients with type 2 diabetes mellitus (T2DM) receiving insulin therapy. Methods: Using a multicenter clinical data warehouse, we analyzed the patients receiving insulin therapy for T2DM who underwent coronary computed tomography angiography (CCTA) for ≥2 times. The patients were divided into two groups according to the presence of DPP‐4i prescription between the two CCTA examinations. The prevalence of OCAD (>50% stenosis on CCTA), new revascularization rates, and changes in the coronary calcium score (CCS) were analyzed. Results: A total of 623 patients were included, and a DPP‐4i was prescribed to 380 (60.9%) patients. The median time difference between the two CCTAs was 39.0 (17.0–61.4) months. Newly developed OCAD at the follow‐up CCTA was detected in 62 (16.3%) patients in the DPP‐4i group and 76 (31.3%) patients in the no DPP‐4i group (p < 0.001). The risk of new OCAD or new revascularization was lower in the DPP‐4i group (19.7% vs. 38.7%; p < 0.001). After propensity score matching, the prevalence of new OCAD (15.9% vs. 29.5%; p = 0.001) and the composite rate of new OCAD or new revascularization (18.7% vs. 37.3%; p < 0.001) were lower in the DPP‐4i group. The change in CCS per year did not differ significantly between the two groups (9.1 [0.1–56.8] vs. 13.5 [0.0–78.6]; p = 0.715). Conclusions: Add‐on DPP‐4i therapy would be beneficial in preventing coronary artery disease progression in patients with T2DM receiving insulin therapy. [ABSTRACT FROM AUTHOR]

Background: The aim of the present study was to investigate the metabolic benefits of saxagliptin and its effects on serum bile acids (BAs) in normal weight and overweight/obese drug‐naïve type 2 diabetes (T2D) patients. Methods: In all, 282 drug‐naïve T2D patients (123 normal weight [NW], with body mass index [BMI] between 19.0 and <25.0 kg/m2; 159 overweight/obese [OW/OB], with BMI ≥25.0 kg/m2) were enrolled in the study and treated with saxagliptin 5 mg daily for 24 weeks. Serum BAs were assayed by liquid chromatography with tandem mass spectrometry. Results: At 24 weeks, HbA1c was significantly reduced in both groups, but the HbA1c levels were lower in the OW/OB than NW group. Moreover, significant decreases were seen at 24 weeks in C‐reactive protein (CRP), aspartate aminotransferase, alanine aminotransferase, waist circumference, and systolic blood pressure in the OW/OB group. Interestingly, cholic acid, glycocholic acid, glycochenodeoxycholic acid, glycodeoxycholic acid (GDCA), and glycoursodeoxycholic acid (GUDCA) were increased in both groups after treatment, whereas chenodeoxycholic acid and deoxycholic acid (DCA) were specifically increased in the OW/OB group. Increased DCA and GDCA concentrations were significantly associated with decreased HbA1c or fasting blood glucose and CRP levels, whereas increased GDCA and GUDCA concentrations were associated with decreased waist circumference in the OW/OB group during treatment. In the NW group, increased GUDCA concentrations were significantly associated with a decrease in HbA1c. Conclusions: Type 2 diabetes patients with OW/OB exhibited greater improvement in glycemic control and additional metabolic benefits after saxagliptin treatment. Saxagliptin significantly increased the BA pool, and DCA and GDCA were associated with metabolic improvements in OW/OB T2D patients. [ABSTRACT FROM AUTHOR]

Background Despite the increasing prevalence of type 2 diabetes mellitus ( T2DM) in Asia, clinical trials for glucose-lowering therapies are often dominated by Caucasian and/or Western populations. The present Phase III randomized placebo-controlled double-blind, 24-week study evaluated the efficacy and safety of the dipeptidyl peptidase-4 inhibitor linagliptin added to metformin in Asian T2DM patients. Methods In all, 306 patients ( n = 265 Chinese; n = 24 Malaysian; n = 17 Filipino), aged 18-80 years with HbA1c between ≥7.0 and ≤10.0% and on metformin therapy were randomized (2:1) to either linagliptin 5 mg daily or placebo added to metformin. Antidiabetes drugs other than metformin were washed out prior to randomization. The primary endpoint was change in mean HbA1c from baseline after 24 weeks. Results Baseline characteristics were well-matched between the groups (overall mean [± SD] HbA1c 8.0 ± 0.8%). Adjusted mean (± SE) HbA1c decreased in the linagliptin and placebo groups by −0.66 ± 0.05 and −0.14 ± 0.07%, respectively (placebo-corrected difference −0.52 ± 0.09%; 95% confidence interval [ CI] −0.70, −0.34; P < 0.0001). In patients with baseline HbA1c ≥8.5%, the placebo-corrected decrease in HbA1c was −0.89 ± 0.17% ( P < 0.0001). Adverse events occurred in similar proportions in the linagliptin and placebo patients (27.3% and 28.0%, respectively) and few were considered drug-related (2.4% and 0.0%, respectively). Hypoglycemia occurred in 1.0% of patients in both groups. Linagliptin therapy was weight neutral. Conclusions Linagliptin 5 mg was efficacious and well tolerated over 24 weeks in Asian patients with T2DM inadequately controlled by metformin. [ABSTRACT FROM AUTHOR]

Objective Dipeptidyl peptidase-4 ( DPP-4) is responsible for degradation of glucagon-like peptide 1 ( GLP-1) and gastric inhibitory polypeptide ( GIP), the endogenous incretins that stimulate glucose-dependent insulin secretion. The objective was to evaluate preclinical profile of a novel DPP-4 inhibitor ZYDPLA1. Methods In vitro inhibition potency and selectivity were assessed using recombinant enzymes and/or plasma. In vivo efficacy was determined in oral glucose tolerance test or mixed meal tolerance test in C57BL/ 6J mice, db/db mice and Zucker fatty rats. Pharmacokinetics/pharmacodynamics was studied in mice, rats, dogs, and non-human primates. Results ZYDPLA1 is a potent, competitive and long acting inhibitor of DPP-4 (Ki 0.0027 μM; Koff 2.3 × 10-4 s-1). ZYDPLA1 was more than 7000-fold selective for recombinant DPP-4 relative to DPP-8 and DPP-9, and more than 60 000-fold selective relative to fibroblast activation protein ( FAP) in vitro. DPP-4 inhibition was comparable across species. In vivo, oral ZYDPLA1 elevated circulating GLP-1 and insulin levels in mice and rats and showed dose-dependent anti-hyperglycemic effect. Anti-hyperglycemic effect was also observed in db/db mice and Zucker fatty rats. ZYDPLA1 showed low clearance, large volume of distribution, and a long half-life with excellent oral bioavailability in all species. It significantly inhibited plasma DPP-4 activity in mice and rats for more than 48 h, and for up to 168 h in dogs and non-human primates. Allometric scaling predicted a half-life in humans of 53 to 166 h. Conclusion ZYDPLA1 is a potent, selective, long-acting oral DPP-4 inhibitor with potential to become once-a-week therapy for treatment of type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Background This work aimed to compare the efficacy of dipeptidyl peptidase- IV ( DPP-4) inhibitors and their impact on β-cell function in Asian and Caucasian patients with type 2 diabetes mellitus. Methods Databases were systematically searched and qualifying studies that compared DPP-4 inhibitors with other antidiabetic medications in type 2 diabetes were included. Results A total of 68 studies were included in the meta-analysis. Comparison of DPP-4 inhibitors with placebo in Asian patients showed a decrease in glycosylated hemoglobin ( HbA1c) favoring DPP-4 inhibitors (weighted mean difference [ WMD], −0.81%; 95% confidence interval [ CI], −0.95% to −0.68%; P < 0.001). Comparison of HbA1c changes between Asian and Caucasian patients showed a significant between-group difference of −0.18% (95% CI, −0.32% to −0.04%; P = 0.011) when compared with placebo. In Asian patients, the homeostatic model assessment for β-cell function ( HOMA- β) was increased with DPP-4 inhibitors compared with placebo ( WMD, 7.90; 95% CI, 4.29 to 11.51; P < 0.001), although to a lesser extent in Caucasian patients. Comparisons between Asian and Caucasian patients showed a significant between-group difference of −4.97 (95% CI, −9.86 to −0.09; P = 0.046) compared with placebo. Body weight increase with DPP-4 inhibitors compared with placebo was comparable in Asian and Caucasian studies ( WMD, 0.37 kg and 0.45 kg and 95% CI, 0.04-0.69 and 0.27-0.62, respectively). Conclusions The glucose-lowering efficacy of DPP-4 inhibitors was greater in Asian patients than in Caucasian patients, although the effect on β-cell function was inferior in Asian patients. The effect of DPP-4 inhibitors on insulin resistance and body weight in Asian patients was comparable with that observed in Caucasian patients. [ABSTRACT FROM AUTHOR]

Background Dipeptidyl peptidase ( DPP)-4 inhibitors and sulfonylureas may have different effects on islet function. We designed a new two-step hyperglycemic clamp to further compare the effects of sitagliptin, saxagliptin, and glimepiride on β-cell function and the incretin effect. Methods The present study was a four-way cross-over open label randomized study. Twelve healthy male subjects were administered a single dose of sitagliptin (100 mg), saxagliptin (5 mg), glimepiride (2 mg) or blank control 2 h before undergoing a two-step hyperglycemic clamp (Step 1: only intravenous glucose was administered; Step 2: i.v. glucose loading was combined with oral glucose consumption). Two-phase insulin secretion, glucagon secretion, and incretin levels were measured during the clamp. Results In Step 1, with i.v. glucose only, there were no differences between the effects of the three drugs on insulin secretion, except that saxagliptin increased second-phase insulin secretion more than glimepiride ( P = 0.007). In Step 2, oral glucose consumption led to an approximate two fold increase in insulin secretion and both gliptins significantly increased first-phase insulin secretion compared with glimepiride ( P = 0.003 for both). Saxagliptin further increased second-phase insulin secretion compared with glimepiride ( P = 0.005) and sitagliptin ( P < 0.001). Both gliptins significantly decreased glucagon secretion and increased active glucagon-like peptide-1 ( GLP-1) compared with glimepiride, especially in Step 2. Conclusions The two-step hyperglycemic clamp appears to be a precise method to assess β-cell function by taking the effect of incretins into consideration. The oral glucose consumption adds to the i.v. glucose infusion, amplifying the differences in the effects of DPP-4 inhibitors and glimepiride on insulin secretion. [ABSTRACT FROM AUTHOR]

Background The aim of the randomized present study was to compare the therapeutic efficacy and safety of a combination of sitagliptin, a dipeptidyl peptidase (DPP)-4 inhibitor, plus insulin glargine (GL + sita) with that of premixed insulin aspart 30 (NOV) for type 2 diabetes (T2D) patients controlled with oral hypoglycemic drugs (HbA1c 7 %-9 %). Methods Sixty-five patients were randomized (1: 1) to the GL + sita (n = 33) and NOV (n = 32) groups and were treated with the combination regimen or premixed insulin twice a day for 16 weeks. The primary endpoint was mean change in HbA1c. Secondary endpoints included fasting blood glucose, blood glucose profiles (seven time points), rate of achieving target HbA1c (<7 % or ≤6.5 %), insulin dose, incidence of hypoglycemia, and body weight. Results After 16 weeks, there was no significant difference in HbA1c between the two groups, although more patients achieved HbA1c <7.0 % in the GL + sita group. There was a significant difference in body weight changes between the GL + sita and NOV groups (−0.45 vs 1.52 kg, respectively; P < 0.001). Mean plasma glucose and the mean amplitude of glycemic excursion were significantly lower in the GL + sita than NOV group ( P < 0.005), as was the incidence of symptomatic hypoglycemia (2.85 % vs. 13.3 %, respectively; P < 0.001). Conclusion The combination of GL + sita greatly improved HbA1c in T2D patients (HbA1c 7 %-9 %) with an efficacy that was equal to that of premixed insulin. Thus, GL + sita treatment is a viable option for patients who fail to achieve glycemic control using oral hypoglycemic drugs. [ABSTRACT FROM AUTHOR]

Background: New therapeutic approaches are needed to improve glycemic control in patients with type 2 diabetes (T2D), a progressive disorder that often requires combination therapy. The present study assessed the efficacy and safety of sitagliptin as add-on therapy to metformin and rosiglitazone in patients with T2D. Methods: The present study was a randomized double-blind placebo-controlled parallel-group 54-week study conducted at 41 sites across North and South America, Europe, and Asia in 278 patients with HbA1c ranging from ≥7.5% to ≤11.0% despite ongoing combination therapy with metformin (≥1500 mg/day) and rosiglitazone (≥4 mg/day). Patients were randomized (2:1) to receive sitagliptin 100 mg or placebo once daily. The main outcome measure was change from baseline in HbA1c at Week 18. Results: Mean baseline HbA1c was 8.8%. The mean placebo-adjusted change from baseline in HbA1c with sitagliptin treatment was −0.7% ( P < 0.001) at Week 18 and −0.8% ( P < 0.001) at Week 54. There were also significant ( P < 0.001) reductions in 2-h post-meal glucose and fasting plasma glucose compared with placebo at Weeks 18 and 54. Significantly higher proportions of sitagliptin- than placebo-treated patients had HbA1c<7.0% at Weeks 18 (22% vs 9%; P = 0.003) and 54 (26% vs 14%; P = 0.015). Changes in body weight and the rates of adverse events overall, hypoglycemia, and gastrointestinal adverse events were similar in the sitagliptin and placebo groups during the 54-week study. Conclusions: In patients with T2D, the addition of sitagliptin for 54 weeks to ongoing therapy with metformin and rosiglitazone improved glycemic control and was generally well tolerated compared with placebo. [ABSTRACT FROM AUTHOR]