Dose-Dependent Effect of Sitagliptin on Carotid Atherosclerosis in Patients with Type 2 Diabetes Mellitus Receiving Insulin Treatment: A Post Hoc Analysis

IntroductionDipeptidyl peptidase-4 (DPP-4) inhibitors reduce blood glucose in a dose-dependent manner, but the dose-dependent effect relationship between DPP-4 inhibitors and atherosclerosis has not been investigated.MethodsPatients with type 2 diabetes mellitus (T2DM) treated with insulin were randomized to the sitagliptin (n = 137) or conventional treatment group (n = 137). In the sitagliptin group, each investigator was allowed to adjust the sitagliptin dose to avoid hypoglycemia. In this post hoc analysis, subjects in the sitagliptin group were divided into two groups based on the average dose of sitagliptin during the study period: greater than or equal to median (higher sitagliptin dose group) or less than median (lower sitagliptin dose group).ResultsIn this study, subjects were divided into three groups: the conventional treatment group (n = 137), lower sitagliptin dose group (n = 42), and higher sitagliptin dose group (n = 95). The higher sitagliptin dose group had a significantly larger reduction in HbA1c (−0.62 ± 1.05%) than the conventional treatment group (−0.20 ± 0.91%, P = 0.007). Over 104 weeks, the higher sitagliptin dose significantly reduced the mean intima media thickness-common carotid artery (IMT-CCA) and left max-IMT-CCA relative to baseline. In addition, the higher sitagliptin dose significantly inhibited the progression in mean-IMT-CCA compared with conventional treatment. Multiple linear regression analysis showed that changes in mean-IMT-CCA and left max-IMT-CCA decreased with higher sitagliptin dose.ConclusionsAddition of sitagliptin to insulin therapy might attenuate the progression of atherosclerosis in patients with T2DM in a dose-dependent manner

Changes in carotid intima-media thickening in patients with type 2 diabetes mellitus: Subanalysis of the Sitagliptin Preventive Study of Intima-Media Thickness Evaluation

Type 2 diabetes mellitus is a risk factor for cardiovascular disease. Both the absolute value and progression of carotid artery intima‐media thickness (IMT) are considered a marker of progression of atherosclerosis. We reported recently that treatment with sitagliptin, a dipeptidyl peptidase‐4 inhibitor, attenuated the progression of carotid IMT in insulin‐treated patients with type 2 diabetes mellitus compared with conventional therapy1. Here, we compared the efficacy of treatment with sitagliptin with that of other modalities on the progression of carotid IMT in prespecified subgroups of the Sitagliptin Preventive Study of Intima‐Media Thickness Evaluation (SPIKE) registered on the University Hospital Medical Information Network Clinical Trials Registry (UMIN000007396)1, 2. The aim of the comparison was to identify the characteristics of patients who benefited most from the sitagliptin treatment in terms of decrease in IMT.The recruits in the original study included 282 insulin‐treated Japanese type 2 diabetes mellitus patients free of past history of apparent cardiovascular disease. They were randomly allocated to either the sitagliptin group (n = 142) or the conventional treatment group (using drugs other than sitagliptin; n = 140). After the exclusion of eight patients, data of 137 patients of the sitagliptin group and 137 of the conventional treatment group were subjected to analysis. The mean‐IMT of the common carotid arteries (mean‐IMT‐CCA) and right and left max‐IMT‐CCA were measured by expert sonographers at the start of the study, and the procedure was repeated after 52 and 104 weeks, as reported previously1, 2. Figure 1 shows differences in treatment‐induced delta change in carotid IMT, relative to baseline in 243 patients whose IMT data were available at baseline and 104 weeks, according to various predefined risk factors for atherosclerosis. The results showed consistent reductions in mean IMT‐CCA and left max IMT‐CCA, but not right max IMT‐CCA, in the sitagliptin group (Figure 1). In particular, a greater reduction in carotid IMT was noted after treatment with sitagliptin in patients with risk factors for cardiovascular disease, such as higher glycated hemoglobin, higher body mass index, longer duration of type 2 diabetes mellitus, use of angiotensin‐converting enzyme inhibitors/angiotensin II receptor blocker, use of statins, worse hypertension and/or hyperlipidemia at baseline, compared with conventional treatment. These data suggest that treatment with dipeptidyl peptidase‐4 inhibitors seems to prevent the progression of carotid atherosclerosis regardless of disease burden. Previous studies showed that treatment with statins and angiotensin‐converting enzyme inhibitors reduces the progression of carotid atherosclerosis in patients with type 2 diabetes mellitus3, 4. In this subgroup analysis, sitagliptin still attenuated the progression of carotid IMT, even in patients who were receiving those therapies. Thus, dipeptidyl peptidase‐4 inhibitors seem to have unique and/or additive anti‐atherosclerotic effects as add‐on therapy to statins and/or angiotensin‐converting enzyme inhibitors/angiotensin II receptor blockers

The Effect of Sitagliptin on the Regression of Carotid Intima-Media Thickening in Patients with Type 2 Diabetes Mellitus: A Post Hoc Analysis of the Sitagliptin Preventive Study of Intima-Media Thickness Evaluation

Background. The effect of dipeptidyl peptidase-4 (DPP-4) inhibitors on the regression of carotid IMT remains largely unknown. The present study aimed to clarify whether sitagliptin, DPP-4 inhibitor, could regress carotid intima-media thickness (IMT) in insulin-treated patients with type 2 diabetes mellitus (T2DM). Methods. This is an exploratory analysis of a randomized trial in which we investigated the effect of sitagliptin on the progression of carotid IMT in insulin-treated patients with T2DM. Here, we compared the efficacy of sitagliptin treatment on the number of patients who showed regression of carotid IMT of ≥0.10 mm in a post hoc analysis. Results. The percentages of the number of the patients who showed regression of mean-IMT-CCA (28.9% in the sitagliptin group versus 16.4% in the conventional group, P = 0.022) and left max-IMT-CCA (43.0% in the sitagliptin group versus 26.2% in the conventional group, P = 0.007), but not right max-IMT-CCA, were higher in the sitagliptin treatment group compared with those in the non-DPP-4 inhibitor treatment group. In multiple logistic regression analysis, sitagliptin treatment significantly achieved higher target attainment of mean-IMT-CCA ≥0.10 mm and right and left max-IMT-CCA ≥0.10 mm compared to conventional treatment. Conclusions. Our data suggested that DPP-4 inhibitors were associated with the regression of carotid atherosclerosis in insulin-treated T2DM patients. This study has been registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN000007396)

The Effect of Sitagliptin on the Regression of Carotid Intima-Media Thickening in Patients with Type 2 Diabetes Mellitus: A Post Hoc Analysis of the Sitagliptin Preventive Study of Intima-Media Thickness Evaluation

Background. The effect of dipeptidyl peptidase-4 (DPP-4) inhibitors on the regression of carotid IMT remains largely unknown. The present study aimed to clarify whether sitagliptin, DPP-4 inhibitor, could regress carotid intima-media thickness (IMT) in insulin-treated patients with type 2 diabetes mellitus (T2DM). Methods. This is an exploratory analysis of a randomized trial in which we investigated the effect of sitagliptin on the progression of carotid IMT in insulin-treated patients with T2DM. Here, we compared the efficacy of sitagliptin treatment on the number of patients who showed regression of carotid IMT of ≥0.10 mm in a post hoc analysis. Results. The percentages of the number of the patients who showed regression of mean-IMT-CCA (28.9% in the sitagliptin group versus 16.4% in the conventional group, P = 0.022) and left max-IMT-CCA (43.0% in the sitagliptin group versus 26.2% in the conventional group, P = 0.007), but not right max-IMT-CCA, were higher in the sitagliptin treatment group compared with those in the non-DPP-4 inhibitor treatment group. In multiple logistic regression analysis, sitagliptin treatment significantly achieved higher target attainment of mean-IMT-CCA ≥0.10 mm and right and left max-IMT-CCA ≥0.10 mm compared to conventional treatment. Conclusions. Our data suggested that DPP-4 inhibitors were associated with the regression of carotid atherosclerosis in insulin-treated T2DM patients. This study has been registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN000007396)

Protocol of a Prospective Observational Study on the Relationship Between Glucose Fluctuation and Cardiovascular Events in Patients with Type 2 Diabetes

IntroductionA recent study demonstrated that large glucose fluctuations were associated with an increased incidence of cardiovascular disease (CVD) in patients with type 2 diabetes mellitus (T2DM) and acute myocardial infarction. However, it is unknown whether glucose fluctuations are related to the incidence of CVD or the progression of atherosclerosis in patients with T2DM with no apparent history of CVD. In this protocol, we will be investigating the relationships of glucose fluctuations evaluated by continuous glucose monitoring (CGM) to the incidence of composite cardiovascular events and the progression of atherosclerosis in patients with T2DM who had no apparent history of CVD.MethodsThis is a prospective, multicenter, 5-year follow-up observational study. Between April 2018 and October 2019, 1000 participants are expected to be recruited at 34 medical institutions. CGM using FreeStyle Libre Pro is useful for evaluating glucose fluctuations by continuously monitoring glucose levels in interstitial fluid for up to 14 days. The primary study outcome is the relationship between fluctuations in glucose levels evaluated by CGM and the incidence of composite cardiovascular events. Secondary outcomes include the relationships of fluctuations in glucose levels evaluated by CGM to changes in carotid intima media thickness evaluated by echography or grayscale median (an index of tissue characteristics of the carotid wall), brachial–ankle pulse wave velocity, development or progression of diabetic retinopathy or nephropathy, quality-of-life-related diabetes therapy, quality of sleep, development of dementia, and autonomic nerve function.Planned OutcomeThis protocol is designed to investigate the relationship between glucose fluctuations and the incidence of composite cardiovascular events. We completed the registration of 1000 participants in March 2019. Thus, results will be available in 2024. We expect that evaluating glucose fluctuations will aid the identification of patients with a high probability of developing CVD.Trial RegistrationClinicalTrials.gov identifier, UMIN000032325

The Influence of Sitagliptin on Treatment-Related Quality of Life in Patients with Type 2 Diabetes Mellitus Receiving Insulin Treatment: A Prespecified Sub-Analysis

IntroductionTreatment-related quality of life (QOL) is an important aspect of diabetes management. Here, we investigated the influence of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on treatment-related QOL in patients with type 2 diabetes mellitus treated with insulin.MethodsThis was a prespecified sub-analysis of the Sitagliptin Preventive Study of Intima-Media Thickness Evaluation (SPIKE). The study population consisted of 71 subjects in the sitagliptin group, and 62 subjects in the conventional group who were treated with insulin. Patients of the sitagliptin group were started on sitagliptin in addition to ongoing insulin therapy. In the conventional group, either increasing the dose of current insulin therapy or the addition of oral hypoglycemic agents other than dipeptidyl peptidase-4 inhibitors was allowed to achieve glycemic control. Treatment-related QOL was evaluated before and 104 weeks after the initiation of the study using the Diabetes Therapy-Related QOL Questionnaire 7 (DTR-QOL7).ResultsForty-five out of 71 subjects in the sitagliptin group and 41 out of 62 subjects in the conventional group filled out the QOL questionnaire at week 104. The DTR-QOL7 score at week 104 was significantly increased from baseline in the sitagliptin group, while that in the conventional group was not changed. However, the changes in score did not differ between the two groups. Change in HbA1c was negatively associated with change in score.ConclusionsOur data suggest that sitagliptin added to insulin treatment was comparable to other treatments in terms of its impact on treatment-related QOL

Characterisation of Ppy-lineage cells clarifies the functional heterogeneity of pancreatic beta cells in mice

Aims/hypothesis Pancreatic polypeptide (PP) cells, which secrete PP (encoded by the Ppy gene), are a minor population of pancreatic endocrine cells. Although it has been reported that the loss of beta cell identity might be associated with beta-to-PP cell-fate conversion, at present, little is known regarding the characteristics of Ppy-lineage cells. Methods We used Ppy-Cre driver mice and a PP-specific monoclonal antibody to investigate the association between Ppy-lineage cells and beta cells. The molecular profiles of endocrine cells were investigated by single-cell transcriptome analysis and the glucose responsiveness of beta cells was assessed by Ca2+ imaging. Diabetic conditions were experimentally induced in mice by either streptozotocin or diphtheria toxin. Results Ppy-lineage cells were found to contribute to the four major types of endocrine cells, including beta cells. Ppy-lineage beta cells are a minor subpopulation, accounting for 12–15% of total beta cells, and are mostly (81.2%) localised at the islet periphery. Unbiased single-cell analysis with a Ppy-lineage tracer demonstrated that beta cells are composed of seven clusters, which are categorised into two groups (i.e. Ppy-lineage and non-Ppy-lineage beta cells). These subpopulations of beta cells demonstrated distinct characteristics regarding their functionality and gene expression profiles. Ppy-lineage beta cells had a reduced glucose-stimulated Ca2+ signalling response and were increased in number in experimental diabetes models. Conclusions/interpretation Our results indicate that an unexpected degree of beta cell heterogeneity is defined by Ppy gene activation, providing valuable insight into the homeostatic regulation of pancreatic islets and future therapeutic strategies against diabetes

Effect of sitagliptin on tissue characteristics of the carotid wall in patients with type 2 diabetes: a post hoc sub-analysis of the sitagliptin preventive study of intima-media thickness evaluation (SPIKE)

BackgroundUltrasonic gray-scale median (GSM) of the carotid wall reflects its composition and low-GSM carotid plaque is considered to be vulnerable. This study aimed to evaluate the effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on the longitudinal change in GSM, an index of the tissue characteristics of the carotid wall, in patients with type 2 diabetes mellitus (T2DM).MethodsThis is a post hoc sub-analysis using data obtained from the SPIKE trial, a randomized controlled trial that demonstrated the beneficial effect of sitagliptin on the progression of carotid intima-media thickness in patients with T2DM. A total of 274 T2DM patients with no past history of apparent cardiovascular disease (137 in the sitagliptin treatment group and 137 in the conventional treatment group) were enrolled. The primary outcome was the change from baseline in mean GSM-CCA during the 104-week treatment period.ResultsThe mean GSM-CCA significantly increased in the sitagliptin treatment group (adjusted ΔGSM = 2.40 ± 1.19 [mean ± SE], p = 0.044) but not in the conventional treatment group (adjusted ΔGSM = 1.32 ± 1.19, p = 0.27). However, there was no significant difference in changes in mean GSM-CCA between the treatment groups.ConclusionsA post hoc sub-analysis suggests that the tissue characteristics of the carotid arterial wall were improved in the sitagliptin treatment group during the 104-week treatment period, but not in the conventional treatment group. However, there was no between-group difference in the changes of GSM values between the two treatment groups. Prespecified studies with large sample sizes would be necessary to confirm our findings

Effects of empagliflozin in patients with chronic kidney disease from Japan: exploratory analyses from EMPA–KIDNEY

Background: EMPA–KIDNEY assessed the effects of empagliflozin 10 mg once daily vs. placebo in 6609 patients with chronic kidney disease (CKD) at risk of progression, including 612 participants from Japan. Methods: Eligibility required an estimated glomerular filtration rate (eGFR) of ≥ 20  Results: Japanese participants had higher levels of albuminuria and eGFR than those from non-Japan regions. During a median of 2.0 year follow-up, a primary outcome occurred in 432 patients (13.1%) in the empagliflozin group and in 558 patients (16.9%) in the placebo group (hazard ratio [HR], 0.72, 95% confidence interval [95%CI] 0.64–0.82; P  Conclusions: Empagliflozin safely reduced the risk of “kidney disease progression or cardiovascular death” in patients with CKD, with consistent effects in participants from Japan