Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes inadequately controlled by glyburide monotherapy

Aim: To evaluate the efficacy and safety of alogliptin, a potent and highly selective dipeptidyl peptidase‐4 (DPP‐4) inhibitor, in combination with glyburide in patients with type 2 diabetes inadequately controlled by sulphonylurea monotherapy. Methods: After a 2‐week screening period, adult patients 18–80 years of age entered a 4‐week run‐in/stabilization period in which they were switched from their own sulphonylurea medication to an equivalent dose of glyburide (open label) plus placebo (single blind). After the run‐in period, patients were randomly assigned to double‐blind treatment with alogliptin 12.5 mg (n = 203), alogliptin 25 mg (n = 198), or placebo (n = 99) for 26 weeks. The primary end‐point was change from baseline to week 26 in glycosylated haemoglobin (HbA1c). Secondary end‐points included clinical response rates and changes in fasting plasma glucose, β‐cell function (fasting proinsulin, insulin, proinsulin/insulin ratio, and C‐peptide, and homeostasis model assessment β‐cell function), body weight, and safety end‐points [adverse events (AEs), clinical laboratory tests, vital signs and electrocardiographic readings]. Results: The study population had a mean age of 57 years and a mean disease duration of 8 years; it was well balanced for gender (52% women) and was mainly white (71%). The mean baseline HbA1c was approximately 8.1% in each group. Significantly greater least squares (LS) mean reductions in HbA1c were seen at week 26 with alogliptin 12.5 mg (?0.38%) and 25 mg (?0.52%) vs. placebo (+0.01%; p < 0.001), and more patients in the alogliptin 25‐mg group had HbA1c levels ≤7.0% at week 26 (34.8%, p = 0.002) vs. placebo (18.2%). Proportionately more patients in the alogliptin 12.5 mg (47.3%) and 25 mg (50.5%) groups had an HbA1c reduction ≥0.5% from baseline compared with patients in the placebo group (26.3%; p < 0.001). Minor improvements in individual markers of β‐cell function were seen with alogliptin, but no significant treatment group differences were noted relative to placebo. Minor LS mean changes in body weight were noted across groups (placebo, ?0.20 kg; alogliptin 12.5 mg, +0.60 kg; alogliptin 25 mg, +0.68 kg). AEs were reported for 63–64% of patients receiving alogliptin and 54% of patients receiving placebo. Few AEs were treatment limiting (2.0–2.5% across groups), and serious AEs (2.0–5.6%) were infrequent, similar across groups, and generally considered not related to treatment. The incidences of hypoglycaemia for placebo, alogliptin 12.5 mg and alogliptin 25 mg groups were 11.1, 15.8 and 9.6% respectively. Conclusions: In patients with type 2 diabetes inadequately controlled by glyburide monotherapy, the addition of alogliptin resulted in clinically significant reductions in HbA1c without increased incidence of hypoglycaemia.     

Angiogenic T cells are decreased in people with type 2 diabetes mellitus and recruited by the dipeptidyl peptidase-4 inhibitor Linagliptin: A subanalysis from a randomized,placebo-controlled trial (RELEASE study)

Angiogenic T (Tang) cells are mediators of vascular repair, and are characterized by surface expression of CXCR4. This receptor for stromal cell-derived factor-1α (SDF-1α) is cleaved by dipeptidyl peptidase-4 (DPP-4). Tang cell levels were investigated in people with type 2 diabetes mellitus (T2DM) compared with matched healthy controls and after treatment with the DPP-4 inhibitor Linagliptin. People with T2DM were randomized to 5 mg/day Linagliptin (n = 20) or placebo (n = 21) for 26 weeks. Tang cell frequency was identified in peripheral blood mononuclear cells (CD3⁺CD31⁺CXCR4⁺) and levels of endothelial progenitor cells (EPCs) (CD34⁺CD133⁺KDR⁺) were also assessed in whole blood. Circulating Tang cell levels were significantly lower in people with T2DM compared with the healthy control group. SDF-1α levels increased significantly in Linagliptin-treated people with T2DM compared to placebo, and a trend was observed in change of Tang cell levels, while EPC count did not change. In conclusion, circulating Tang cell levels were considerably lower in people with T2DM, while a trend was observed in recruitment of Tang cells after 26 weeks of treatment with Linagliptin. These data suggest that DPP-4 inhibitors may potentially exert beneficial effects on bone marrow-driven vascular repair.     

Mechanisms of action of the dipeptidyl peptidase-4 inhibitor vildagliptin in humans

Inhibition of dipeptidyl peptidase-4 (DPP-4) by vildagliptin prevents degradation of glucagon-like peptide-1 (GLP-1) and reduces glycaemia in patients with type 2 diabetes mellitus, with low risk for hypoglycaemia and no weight gain. Vildagliptin binds covalently to the catalytic site of DPP-4, eliciting prolonged enzyme inhibition. This raises intact GLP-1 levels, both after meal ingestion and in the fasting state. Vildagliptin has been shown to stimulate insulin secretion and inhibit glucagon secretion in a glucose-dependent manner. At hypoglycaemic levels, the counterregulatory glucagon response is enhanced relative to baseline by vildagliptin. Vildagliptin also inhibits hepatic glucose production, mainly through changes in islet hormone secretion, and improves insulin sensitivity, as determined with a variety of methods. These effects underlie the improved glycaemia with low risk for hypoglycaemia. Vildagliptin also suppresses postprandial triglyceride (TG)-rich lipoprotein levels after ingestion of a fat-rich meal and reduces fasting lipolysis, suggesting inhibition of fat absorption and reduced TG stores in non-fat tissues. The large body of knowledge on vildagliptin regarding enzyme binding, incretin and islet hormone secretion and glucose and lipid metabolism is summarized, with discussion of the integrated mechanisms and comparison with other DPP-4 inhibitors and GLP-1 receptor activators, where appropriate.     

Disodium ascorbyl phytostanyl phosphate reduces plasma cholesterol concentrations and atherosclerotic lesion formation in apolipoprotein E-deficient mice

Disodium ascorbyl phytostanyl phosphate (FM-VP4) consists of ascorbic acid covalently bound to phytostanols by a phosphodiester linkage and is derived as the disodium salt. The purpose of this study was to evaluate the lipid-lowering and antiatherosclerotic properties of FM-VP4 following administration to apolipoprotein E (ApoE)-deficient mice. Four-week-old male C57BL/6J mice with a homozygous deletion of the ApoE gene (apolipoprotein E knock-out) were administered 0 (control), 0.1%, 0.5%, 1.0%, and 2.0% (wt/vol) FM-VP4 in their drinking water or 2.0% FM-VP4 (wt/wt) in their diet for 12 consecutive weeks. All animals received a standard mouse chow diet consisting of 9.0% (wt/wt) fat and 0.2% (wt/wt) cholesterol. Plasma cholesterol and triglyceride levels were determined at baseline and at 4-week intervals (4, 8, and 12 weeks) throughout the term of the study. At the end of the study, mice were killed using CO(2) gas, and blood was taken from the heart. The heart and aorta were removed and sections of the aortic roots were stained with oil red O (ORO) and Movat's stain. The lesions found in this area were measured using a computer-assisted image analysis. Consumption of FM-VP4 by either food or drinking water routes was associated with an approximately 75% reduction in total plasma cholesterol levels and a 75% decrease in aortic atherosclerotic lesion area in ApoE-deficient mice over 12 weeks compared to controls. A trend in decreasing plasma triglyceride levels was also observed. Taken together these data suggest that FM-VP4 has both lipid-lowering and antiatherosclerotic properties following 12-week administration to ApoE-deficient mice.     

Long-term inhibition of dipeptidyl peptidase-4 in Alzheimer’s prone mice

We tested here the impact of a long-term inhibition of dipeptidyl peptidase-4 (DPP-4) with sitagliptin on the deposition of amyloid-β within the brain and deficits in memory-related behavioral paradigms in a model of Alzheimer’s disease (AD): double transgenic mice B6.Cg-Tg(APPswe,PSEN1dE9)85Dbo/J. Mice began to receive sitagliptin at 7 months of age. Three different dose of sitagliptin (5, 10 and 20 mg/kg), were administered daily for 12 weeks by gastric gavage.     

Wound healing effects of dipeptidyl peptidase-4 inhibitors: An emerging concept in management of diabetic foot ulcer—A review

ObjectiveDipeptidyl peptidase-4 (DPP-4) inhibitors have a well-known effect on glycaemic control in patients with diabetes but little is known on their wound healing role in this group of population. This paper reviews the effects of DPP-4 inhibitors on wound healing of diabetic foot ulcers.MethodsPublished data on effects and mechanism of DDP-4 inhibitors on wound healing were derived from Medline, PubMed and Google Scholar search of English language literature from 1994 to 2014 using the key words such as “DPP-4 inhibitors”, “endothelial healing” “diabetes” and “chronic ulcers”.ResultsDPP-4 inhibitors show a potential benefit in processes of wound healing in diabetic chronic foot ulcers. The enzyme inhibitors promote recruitment of endothelial progenitor cells and allow the final scaffolding of wounds. Furthermore DPP-4 inhibitors augment angiogenesis and have widespread effects on optimising the immune response to persistent hypoxia in chronic diabetes wounds.ConclusionDPP-4 inhibitors show promise in the local wound healing of diabetic foot ulcers in addition to its already established glycaemic control. In the light of high rate of amputations due to non-healing ulcers with profound psychological and economical liability, more investigations on the usefulness of DPP-4 inhibitors in the high risk diabetes population are needed.     

Dipeptidyl peptidase-4 inhibitor use and risk of diabetic retinopathy: A population-based study

Aims

This study examined whether dipeptidyl peptidase (DPP)-4 inhibitor use is beneficial or harmful to diabetic retinopathy (DR) compared with other glucose-lowering agents in patients with type 2 diabetes (T2D).

DPP-4抑制剂的作用机制及在2型糖尿病治疗中的应用

α及母细胞功能障碍在2型糖尿病的发生中发挥重要作用.二肽基肽酶4( DPP-4)抑制剂是一类基于肠促胰素的新型的口服降糖药物,通过增加内源性活性胰升糖素样肽-1( GLP-1)及葡萄糖依赖性促胰岛素分泌多肽(GIP)水平改善α及β细胞功能障碍,表现为α及β细胞对葡萄糖的敏感性增加,葡萄糖依赖性地促进胰岛素分泌并抑制胰升糖素分泌.同时还具有增加胰岛素敏感性及调节血脂代谢等胰腺外作用.并具有较少发生低血糖,对体重的影响中性,不影响胃排空等特点.临床研究证实其无论单药还是与其他药物联合使用均具有较高的有效性及良好的安全性和耐受性.     

Evidence-based treatment of hyperglycaemia with incretin therapies in patients with type 2 diabetes and advanced chronic kidney disease

Type 2 diabetes is the leading cause of chronic kidney disease (CKD). The prevalence of CKD is growing in parallel with the rising number of patients with type 2 diabetes globally. At present, the optimal approach to glycaemic control in patients with type 2 diabetes and advanced CKD (categories 4 and 5) remains uncertain, as these patients were largely excluded from clinical trials of glucose-lowering therapies. Nonetheless, clinical trial data are available for the use of incretin therapies, dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists, for patients with type 2 diabetes and advanced CKD. This review discusses the role of incretin therapies in the management of these patients. Because the presence of advanced CKD in patients with type 2 diabetes is associated with a markedly elevated risk of cardiovascular disease (CVD), treatment strategies must include the reduction of both CKD and CVD risks because death, particularly from cardiovascular causes, is more probable than progression to end-stage kidney disease. The management of hyperglycaemia is essential for good diabetes care even in advanced CKD. Current evidence supports an individualized approach to glycaemic management in patients with type 2 diabetes and advanced CKD, taking account of the needs of each patient, including the presence of co-morbidities and concomitant therapies. Although additional studies are needed to establish optimal strategies for glycaemic control in patients with type 2 diabetes and advanced CKD, treatment regimens with currently available pharmacotherapy can be individually tailored to meet the needs of this growing patient population.     

Cardiovascular efficacy and safety of dipeptidyl peptidase-4 inhibitors: A meta-analysis of cardiovascular outcome trials

BACKGROUND Dipeptidyl peptidase-4(DPP-4) inhibitors are a generally safe and well tolerated antidiabetic drug class with proven efficacy in type 2 diabetes mellitus(T2 DM). Recently, a series of large, randomized controlled trials(RCTs) addressing cardiovascular outcomes with DPP-4 inhibitors have been published.AIM To pool data from the aforementioned trials concerning the impact of DPP-4 inhibitors on surrogate cardiovascular efficacy outcomes and on major cardiac arrhythmias.METHODS We searched PubMed and grey literature sources for all published RCTs assessing cardiovascular outcomes with DPP-4 inhibitors compared to placebo until October 2020. We extracted data concerning the following "hard" efficacy outcomes: fatal and non-fatal myocardial infarction, fatal and non-fatal stroke, hospitalization for heart failure, hospitalization for unstable angina, hospitalization for coronary revascularization and cardiovascular death. We also extracted data regarding the risk for major cardiac arrhythmias, such as atrial fibrillation, atrial flutter, ventricular fibrillation and ventricular tachycardia.RESULTS We pooled data from 6 trials in a total of 52520 patients with T2 DM assigned either to DPP-4 inhibitor or placebo. DPP-4 inhibitors compared to placebo led to a non-significant increase in the risk for fatal and non-fatal myocardial infarction [risk ratio(RR) = 1.02, 95%CI: 0.94-1.11, I2 = 0%], hospitalization for heart failure(RR = 1.09, 95%CI: 0.92-1.29, I2 = 65%) and cardiovascular death(RR = 1.02, 95%CI: 0.93-1.11, I2 = 0%). DPP-4 inhibitors resulted in a non-significant decrease in the risk for fatal and non-fatal stroke(RR = 0.96, 95%CI: 0.85-1.08, I2 = 0%) and coronary revascularization(RR = 0.99, 95%CI: 0.90-1.09, I2 = 0%), Finally, DPP-4 inhibitors demonstrated a neutral effect on the risk for hospitalization due to unstable angina(RR = 1.00, 95%CI: 0.85-1.18, I2 = 0%). As far as cardiac arrhythmias are concerned, DPP-4 inhibitors did not significantly affect the risk for atrial fibrillation(RR = 0.95, 95%CI: 0.78-1.17, I2 = 0%), while they were associated with a significant increase in the risk for atrial flutter, equal to 52%(RR = 1.52, 95%CI: 1.03-2.24, I2 = 0%). DPP-4 inhibitors did not have a significant impact on the risk for any of the rest assessed cardiac arrhythmias.CONCLUSION DPP-4 inhibitors do not seem to confer any significant cardiovascular benefit for patients with T2 DM, while they do not seem to be associated with a significant risk for any major cardiac arrhythmias, except for atrial flutter. Therefore, this drug class should not be the treatment of choice for patients with established cardiovascular disease or multiple risk factors, except for those cases when newer antidiabetics(glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors) are not tolerated, contraindicated or not affordable for the patient.     

Angiotensin II type 1 receptor blocker telmisartan suppresses superoxide production and reduces atherosclerotic lesion formation in apolipoprotein E-deficient mice

Angiotensin II is involved in the process of atherosclerosis and stimulates superoxide production from cardiovascular cells. We examined the effect of telmisartan, an angiotensin II type 1 receptor blocker, on atherosclerosis. We chronically treated apolipoprotein E-deficient mice with two different doses of telmisartan dissolved in drinking water (0.3 and 3 mg/kg) starting from 4 weeks of age for 12 weeks. Lipid contents were not different in both telmisartan-treated groups compared with control group. Systolic blood pressure was significantly reduced with 3 mg/kg, but unchanged with 0.3 mg/kg. The total atherosclerotic lesion size at the aortic sinus was reduced with 0.3 mg/kg compared with control, and additional reduction was proved with 3 mg/kg. The fibrotic change was not different among three groups, but MOMA-2-, malondialdehyde-, 4-hydroxy-2-nonenal-immunostained areas were reduced by telmisartan. As the mechanism, we revealed that both doses of telmisartan markedly reduced superoxide production from in situ vessels assessed by lucigenin-enhanced chemiluminescence and dihydroethidium staining. And NAD(P)H dependent oxidase activity in vessels was reduced by telmisartan. Further, 8-iso-prostaglandin F2alpha level, a systemic oxidative stress marker, obtained from urine and plasma samples were significantly reduced by telmisartan. Telmisartan reduced atherosclerosis in apolipoprotein E-deficient mice at least partly via the suppression of oxidative stress.     

Improved glycaemic control with dipeptidyl peptidase-4 inhibition in patients with type 2 diabetes: vildagliptin (LAF237) dose response

OBJECTIVE: A novel treatment option for diabetic patients is the enhancement of incretin hormone activity by inhibition of the enzyme dipeptidyl peptidase-4 (DPP-4). This study was designed to establish a dose of the DPP-4-inhibitor vildagliptin (LAF237) that was effective in reducing HbA1c levels and was safe and well tolerated in patients with type 2 diabetes. PATIENTS AND METHODS: The study of 279 patients with type 2 diabetes consisted of a 4-week run-in phase where patients received placebo and a 12-week active treatment phase where they received one of the following dosages of vildagliptin: 25 mg twice daily, 25, 50 or 100 mg once daily (qd), or placebo. RESULTS: There was a statistically significant reduction in HbA1c levels in the vildagliptin 50 mg qd (p=0.003) and 100 mg qd groups (p=0.004) compared with the placebo group. The mean 4-h postprandial glucose level was significantly reduced from placebo in the vildagliptin 50 mg qd group (p = 0.012) and mean 4-h postprandial insulin was significantly increased from baseline vs. placebo in the vildagliptin 100 mg qd group (p=0.022). The assessment of beta-cell function (HOMA-B) was significantly increased in the vildagliptin 100 mg qd treatment group (p=0.007). The incidence of adverse events was similar in all treatment groups including placebo. CONCLUSIONS: Vildagliptin, at 50 and 100 mg qd, was effective in reducing HbA1c levels compared with placebo in patients with type 2 diabetes. Vildagliptin at dosages up to 100 mg qd appeared safe and well tolerated.     

2型糖尿病颈动脉粥样硬化患者血清二肽基肽酶4和氧化低密度脂蛋白水平改变

目的探讨T2DM合并颈动脉粥样硬化(CAS)患者血清二肽基肽酶4(DPP-4)和氧化低密度脂蛋白(ox-LDL)水平改变。方法回顾性分析2020年1~10月于宜昌市第二人民医院内分泌科住院的T2DM患者120例,根据颈动脉彩超检查颈动脉内膜中层厚度及直接观察有无动脉粥样斑块形成,分为单纯T2DM组(T2DM,n=60)及T2DM合并CAS组(CAS,n=60),同期选取性别、年龄匹配的本院体检健康者30名为正常对照(NC)组。分析各组血清DPP-4、ox-LDL指标差异。结果CAS、T2DM组血清DPP4、ox-LDL水平高于NC组(P<0.05或P<0.01)。CAS组血清DPP-4、ox-LDL水平高于T2DM组(P<0.05或P<0.01)。Spearman相关分析显示,T2DM患者血清DPP-4水平与ox-LDL、HbA₁c、HOMA-IR、CIMT呈正相关(P<0.05或P<0.01),与HDL-C呈负相关(P<0.05)。Logistic回归分析结果显示,DPP-4、ox-LDL是T2DM合并CAS的危险因素。结论T2DM合并CAS患者血清DPP-4、ox-LDL水平升高,是T2DM合并CAS的危险因素。