Dipeptidyl peptidase 4 inhibitor sitagliptin decreases myocardial fibrosis and modulates myocardial insulin signaling in a swine model of chronic myocardial ischemia.

Although both clinical data and animal models suggest cardiovascular benefits following administration of Dipeptidyl Peptidase 4 (DPP-4) inhibitors, the underlying mechanisms remain unclear. We therefore sought to evaluate the effect of the DPP-4 inhibitor sitagliptin on myocardial fibrosis, and insulin signaling in chronic myocardial ischemia using a swine model. An ameroid constrictor placement on the left coronary circumflex artery of thirteen Yorkshire swine to model chronic myocardial ischemia. After two weeks of recovery, swine were assigned to one of two groups: control (CON, n = 8), or sitagliptin 100mg daily (SIT, n = 5). After 5 weeks of treatment, the swine underwent terminal harvest with collection of myocardial tissue. Fibrosis was quantified using Masson's trichrome. Protein expression was quantified by Immunoblotting. Trichrome stain demonstrated a significant decrease in perivascular and interstitial fibrosis in the SIT group relative to CON (all p<0.05). Immunoblot showed a reduction in Jak2, the pSTAT3 to STAT 3 Ratio, pSMAD 2/3, and SMAD 2/3, and an increase in STAT 3 in the SIT group relative to CON (all p<0.05). SIT treatment was associated with increased expression of insulin receptor one and decreased expression of makers for insulin resistance, including phospho-PKC- alpha, RBP-4, SIRT1, and PI3K (p<0.05). Sitagliptin results in a reduction in perivascular and interstitial fibrosis and increased insulin sensitivity in chronically ischemic swine myocardium. This likely contributes to the improved cardiovascular outcomes seen with DPP-4 inhibitors.

Sitagliptin alleviates renal steatosis and endoplasmic reticulum stress in high fat diet-induced obese rats by targeting SREBP-1/CD36 signaling pathway.

High fat diet (HFD) consumption can cause dysregulation of glucose and lipid metabolism, coupled with increased ectopic lipid deposition in renal tissue leading to steatosis and dysfunction. Sitagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor clinically used for type II diabetes therapy; however its effect on renal steatosis in obese state is still uncertain. Herein, obesity was induced by feeding male Wistar rats HFD for 18 weeks, thereafter received either drug vehicle, or sitagliptin (10 mg/kg, PO) along with HFD for further 6 weeks and compared with age-matched rats receiving normal chow diet (NCD). After 24 weeks, serum and kidneys were collected for histological and biochemical assessments. Compared to NCD-fed group, HFD-fed rats displayed marked weight gain, increased fat mass, insulin resistance, dyslipidemia, impaired kidney functions and renal histological alterations. Sitagliptin effectively ameliorated obesity and related metabolic perturbations and improved kidney architecture and function. There were increased levels of triglycerides and cluster of differentiation 36 (CD36) in kidneys of obese rats, that were lowered by sitagliptin therapy. Sitagliptin significantly repressed the expression of lipogenesis genes, while up-regulated genes involved in mitochondrial biogenesis and fatty acid oxidation in kidneys of HFD-fed rats. Sitagliptin was found to induce down-regulation of endoplasmic reticulum (ER) stress and apoptotic markers in kidneys of obese rats. These findings together may emphasize a novel concept that sitagliptin can be an effective therapeutic approach for halting obesity-related renal steatosis and CKD.

[Cardiovascular safety of sitagliptin added to metformin in real world patients with type 2 diabetes].

OBJECTIVE: To assess the safety of sitagliptin added to metformin on cardiovascular adverse events in real world patients with type 2 diabetes mellitus (T2DM). METHODS: Real world data from Yinzhou Regional Health Care Database were used to select T2DM patients with diagnosis and treatment records in the platform from January 1, 2017 to December 31, 2022. According to drug prescription records, the patients were divided into metformin plus sitagliptin group (combination group) and metformin monotherapy group(monotherapy group). A series of retrospective cohorts were constructed according to the index date.Finally, full retrospective cohorts were constructed according to propensity score model, including baseline covariates that might be related to outcomes, to match the subjects in the combination group and monotherapy group for the purpose of increasing the comparability of baseline characteristics. The participants were followed up from the index date until the first occurrence of the following events: Diagnosis of outcomes, death, or the end of the study period (December 31, 2022). Cox proportional risk model was used to estimate the hazard ratio(HR)and 95% confidence interval (CI) of sitagliptin added to metformin on 3-point major adverse cardiovascular events (3P-MACE) combination outcome and secondary cardiovascular outcomes. RESULTS: Before propensity score matching, the proportion of the patients in combination group using insulin, α glucosidase inhibitors, sodium-glucose transporter 2 inhibitors (SGLT-2I) and glienides at baseline was higher than that in monotherapy group, and the baseline fasting blood glucose (FBG) and hemoglobin A1c (HbA1c) levels in combination group were higher than those in monotherapy group. After propensity score matching, 5 416 subjects were included in the combination group and the monotherapy group, and baseline characteristics were effectively balanced between the groups. The incidence densities of 3P-MACE were 6.41/100 person years and 6.35/100 person years, respectively. Sitagliptin added to metformin did not increase or decrease the risk of 3P-MACE compared with the metformin monotherapy (HR=1.00, 95% CI: 0.91-1.10). In secondary outcomes analysis, the incidence of cardiovascular death was lower in the combination group than in the monotherapy group (HR=0.59, 95% CI: 0.41-0.85), and no association was found between sitagliptin and the risk of myocardial infarction and stroke (HR=1.12, 95% CI: 0.89-1.41; HR=0.99, 95% CI: 0.91-1.12). CONCLUSION: In T2DM patients in Yinzhou district of Ningbo, compared with metformin alone, sitagliptin added to metformin may reduce the risk of cardiovascular death, and do not increase the incidence of overall cardiovascular events. The results of this study can provide real-world evidence for post-marketing cardiovascular safety evaluation of sitagliptin.

Effect of sitagliptin therapy on IL-29 and its associated signaling molecules in patients with type 2 diabetes mellitus.

OBJECTIVE: The potential immunoregulatory capacity of sitagliptin on interleukin-29 (IL-29) and genes involved in its intracellular pathway were explored in type 2 diabetes mellitus (T2D). MATERIALS AND METHODS: T2D patients treated with six months of sitagliptin (Sita+), patients not treated with sitagliptin (Sita-), and healthy controls (HCs) were included. IL-29 levels in the supernatant of stimulated mononuclear immune cells was determined with ELISA. The mRNA expression levels of IL-29, FOS, JUN, NF-AT2, NF-KB1, STAT1-2, IRF1, IRF3, IRF7, and IRF9 was assessed with real-time qPCR. RESULTS: Increased protein and gene levels of IL-29 were observed in Sita- group compared to HCs (p < 0.001 and p = 0.026), while those levels were diminished in Sita+ group in comparison with Sita- group (p < 0.001 and p = 0.008). Expression of FOS, NF-AT2 and NF-KB1 in Sita- patients was higher than HCs (p = 0.018, p = 0.021, and p = 0.001). A significant decrease in expression of FOS, NF-AT2, and NF-KB1 was found in Sita+ group versus Sita- parients (p = 0.027, p = 0.003, and p = 0.002). In Sita- patients, IL-29 levels were correlated to glucose metabolism parameters including FPG and HbA1c (p < 0.05 for all). CONCLUSION: Sitagliptin administration has a regulatory effect on the aggressive expression of IL-29 and its signaling molecules including FOS, NF-AT2 and NF-KB1 in T2D.

Efficacy and tolerability of initial triple combination therapy with metformin, dapagliflozin and saxagliptin compared with stepwise add-on therapy in drug-naïve patients with type 2 diabetes (TRIPLE-AXEL study): A multicentre, randomized, 104-week, open-label, active-controlled trial.

AIM: To evaluate the efficacy and tolerability of an initial triple combination therapy (TCT) compared with conventional stepwise add-on therapy (SAT) in patients with newly diagnosed type 2 diabetes (T2D). MATERIALS AND METHODS: This multicentre, randomized, 104-week, open-label trial randomized 105 patients with drug-naïve T2D (with HbA1c level ≥ 8.0%, < 11.0%) to the TCT (1000 mg of metformin, 10 mg of dapagliflozin and 5 mg of saxagliptin once daily) or SAT (initiated with metformin, followed by glimepiride and sitagliptin) groups. The primary outcome was the proportion of patients who achieved an HbA1c level of less than 6.5% without hypoglycaemia, weight gain of 5% or higher, or discontinuation of drugs because of adverse events at week 104. RESULTS: HbA1c reduction from baseline at week 104 was similar between the groups (the least squares mean change was -2.56% in the TCT group vs. -2.75% in the SAT group). The primary outcome was achieved in 39.0% and 17.1% of the TCT and SAT groups, respectively, with a risk difference of 22.0 (95% confidence interval 3.0, 40.8; P = .027). HbA1c level less than 6.5% at week 104 was 46.3% in both the TCT and SAT groups, whereas the incidence of hypoglycaemia, weight gain, or discontinuation of drugs was 16.7% and 62.0% in the TCT and SAT groups, respectively (P < .001). TCT was well-tolerated and had fewer adverse events than SAT. CONCLUSIONS: Among newly diagnosed patients with T2D, initial TCT effectively lowered HbA1c levels with higher tolerability and safety than SAT for 104 weeks, suggesting a novel strategy for initial combination therapy in T2D patients.

Individual dipeptidyl peptidase-4 inhibitors and acute kidney injury in patients with type 2 diabetes: A systematic review and network meta-analysis.

This network meta-analysis of randomized controlled trials aimed to determine whether any individual dipeptidyl peptidase-4 (DPP-4) inhibitors increase the risk of acute kidney injury (AKI). The Medical Literature Analysis and Retrieval System Online via PubMed, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov were systematically searched to identify relevant studies. The primary outcome was AKI. A frequentist network meta-analysis was performed using a random-effects model to account for heterogeneity. Twenty-nine studies involving 56 117 participants were included. There were 918 cases of AKI (1.63%). The risk of bias was generally considered to be low. The only DPP-4 inhibitor that significantly increased the frequency of AKI when compared with placebo was sitagliptin (risk ratio 1.65, 95% confidence interval 1.22-2.23). However, because one study showed significant outliers in the funnel plot, in a highly heterogeneous population composed solely of patients undergoing surgery for coronary artery bypass graft, we conducted a post-hoc sensitivity analysis to exclude this study. The results showed no statistically significant difference in the risk of AKI between sitagliptin and placebo. Individual DPP-4 inhibitors do not appear to increase the risk of AKI. However, sitagliptin may be associated with AKI in patients with underlying severe cardiovascular disease.

(NDMA) METFORMIN AND (NTTP) SITAGLIPTIN INDUCED CUTANEOUS MELANOMAS: LINKS TO NITROSOGENESIS, NITROSO-PHOTOCARCINOGENESIS, ONCOPHARMACOGENESIS AND THE METABOLIC REPROGRAMMING.

Changing the vision, understanding, interpretation and analysis of certain data or scientific dilemmas is what is able to change the status quo and revitalize a mission, an impulse or important thoughts, thus creating the conditions for it to increase immensely the chances of bringing it to success. Or, following Albert Einstein's postulate: ˝We cannot solve our problems with the same thinking we used when we created them˝, we should think: ˝Where does the road to success start? How do we solve or neutralize a problem? ˝ And the answer is: ˝ By taking a consistent and systematic approach, analyzing each component! And we eliminate every possibility of negative influence.˝ These thoughts apply with full force to cancer rates in general, but also to melanoma rates in particular: the murderous tempo of globalization and modernization in medicine has not yet led to the desired decrease in these rates; on the contrary, they are rising headlong and remain largely unpredictable and difficult to regulate. The conclusion is that a solution should be sought by refracting light through another prism: that of Nitrosogenesis and Pharmaco-Oncogenesis. A step-by-step and systematic approach to solving a problem requires patience, determination, and perseverance. As this perseverance is needed mainly to overcome the general ignorance, neglect, disinterest, uneducation and uncertainty of others, rather than doubt in one's own thesis, analysis, and the need for an active approach. Careful analysis of concepts such as ˝Drug Mediated Nitrosogenesis˝ and ˝Onco-pharmacogenesis/Pharmaco-oncogenesis˝ of skin cancer would certainly contribute to the elucidation of skin carcinogenesis in the context of polymedication of the contamination and polymorbidity worldwide. The FDA has already in 2019 taken this much needed first step of universal awareness and its ˝arm˝ has been taken seriously and responsibly solely by dermatologists and dermatosurgeons. It was this guild and only this guild that launched its independent, never-ending observations, logically grounded (hypo)theses, remaining to date confirmatory, unshakable, and enigmatic regarding the unit: intake of potentially contaminated medication and subsequent development of melanomas. It is this and only this branch of the medical guild that has also become the guarantor of safety and objectivity in science, and thus of safety in the fight for survival of a huge number of skin cancer patients. Contaminated oral antidiabetic drugs in the face of Metformin and Sitagliptin do not make an exception in this respect. Similarly to cutaneous melanomas occurring (and published in the scientific literature) after combined intake (or monomedication) of/ between ranitidine, valsartan, olmesartan, candesartan, telmisartan, irbesartan, losartan, enalapril, lisinopril, perindopril, hydrochlorothiazide, nifedipine, amlodipine, propafenone, bisoprolol, nebivolol, melitracen and a number of others, we inform about another rare but not unexpected clinical observation: occurrence of cutaneous melanomas after taking another class of drugs- oral antidiabetic ones. Or after the intake of nitrosamine-contaminated antidiabetic drugs. And whether this contamination is "real or potential" is left to regulators and manufacturers to decide. We accept it as `real-potential' or `potentially-real' because of the fact that neither the regulators nor the manufacturers know what it is or whether it is there or how it arose. The data shared in patients one and two in the presented scientific work are confirmatory in relation to the potential pathogenetic action of nitrosamine contaminated drugs such as 1) bisoprolol/ nebivolol/ candesartan/ hydrochlorothiazide and amlodipine, as well as 2) furosemide in the direction of cutaneous melanoma. Patient 3 in fact also represents the first formally described patient with subsequent melanoma development worldwide, having developed it following intake of potentially/actually nitrosamine-contaminated metformin and metformin/sitagliptin (both drugs are themed in the FDA's Potentially Contaminated Drug Bulletin: 1) metformin, multiple times between 2020-21, due to its contamination with NDMA and 2) sitagliptin, as of September 2022, due to its contamination with NTTP). It should not be seen as surprising to anyone that the intake of relatively similar carcinogens/nitrosamines or NDSRIs, but as an unofficial component of heterogeneous drugs, produces a relatively monomorphic clinical picture- that of cutaneous melanoma. Or to put it metaphorically: ˝The wolf changes its hair, but not its mood˝. A carcinogen remains a carcinogen, regardless of whether it is ingested in a lemonade, a tablet, a sandwich, or a bonbon. Similarly to the intake of nitrosamines in food. Future studies should address the important tasks/dilemmas to elucidate 1) the phototoxic/photocarcinogenic effect of unmetabolized nitrosamines identified in drug formulations; 2) the phototoxic/photocarcinogenic effect of DNA adducts generated after their metabolization, and 3) the availability of specific DNA adducts in lesional/tumor tissue and blood of patients after ingestion of nitroso-containing drug formulations. This level of evidence is likely to lead to a reconsideration of the arguments for the introduction of permanent elimination regimes for nitrosamines in medicines. Metabolic reprogramming (and its relationship to UVB radiation) due to the availability of nitrosamines in cigarette smoke is also currently a proven reality. Based on the available clinicopathological correlations, we believe that nitrosamines in drugs have a similar effect and are part of the key pathway activating skin carcinogenesis under the influence of solar radiation. Intake of contaminated medication is associated with skin cancer generation and progression. It is up to regulators and manufacturers to justify the merits and benefits of the self-imposed presence of carcinogens in drugs or the benefits of such drugs. Apart from the "cancer-generating benefit", of course, which is already widely known. And let us not forget that: "A lie stops being a lie and becomes a truth the moment it is officially refuted".

Prediction of glycosylated hemoglobin level in patients with cardiovascular diseases and type 2 diabetes mellitus with respect to anti-diabetic medication.

Blood glycosylated hemoglobin level can be affected by various factors in patients with type 2 diabetes and cardiovascular diseases. Frequent measurements are expensive, and a suitable estimation method could improve treatment outcomes. Patients and methods: 93 patients were recruited in this research. We analyzed a number of parameters such as age, glucose level, blood pressure, Body Mass Index, cholesterol level, echocardiography et al. Patients were prescribed metformin. One group (n=60) additionally was taking sitagliptin. We applied eight machine learning methods (k nearest neighbors, Random Forest, Support Vector Machine, Extra Trees, XGBoost, Linear Regression including Lasso, and ElasticNet) to predict exact values of glycosylated hemoglobin in two years. Results: We applied a feature selection approach using step-by-step removal of them, Linear Regression on remaining features, and Pearson's correlation coefficient on the validation set. As a result, we got four different subsets for each group. We compared all eight Machine Learning methods using different hyperparameters on validation sets and chose the best models. We tested the best models on the external testing set and got R2 = 0.88, C Index = 0.857, Accuracy = 0.846, and MAE (Mean Absolute Error) = 0.65 for the first group, R2 = 0.86, C Index = 0.80, Accuracy = 0.75, and MAE = 0.41 for the second group. Conclusion: The resulting algorithms could be used to assist clinical decision-making on prescribing anti-diabetic medications in pursuit of achieving glycemic control.

Efficacy and safety of sitagliptin with basal-plus insulin regimen versus insulin alone in non-critically ill hospitalized patients with type 2 diabetes: SITA-PLUS hospital trial.

AIMS: To compare the efficacy and safety of basal-plus (BP) insulin regimen with or without sitagliptin in non-critically ill patients with type 2 diabetes (T2D). METHODS: This open-label, randomized clinical trial included inpatients with a previous diagnosis of T2D and blood glucose (BG) between 180 and 400 mg/dL. Participants received basal and correctional insulin doses (BP regimen) either with or without sitagliptin. The primary outcome was the difference in the mean daily BG among the groups. RESULTS: Seventy-six patients (mean age 60 years, 64 % men) were randomized. Compared with BP insulin therapy alone, the sitagliptin-BP combination led to a lower mean daily BG (158.8 vs 175.0 mg/dL, P = 0.014), a higher percentage of readings within a BG range of 70-180 mg/dL (75.9 % vs 64.7 %, P < 0.001), and a lower number of BG readings >180 mg/dL (P < 0.001). Sitagliptin-BP resulted in fewer basal and supplementary insulin doses (P = 0.024 and P = 0.017, respectively) and lower daily insulin injections (P = 0.023) than those with insulin alone. The proportion of patients with hypoglycemia was similar in the two groups. CONCLUSIONS: For inpatients with T2D and hyperglycemia, the sitagliptin and BP regimen combination is safe and more effective than insulin therapy alone. CLINICALTRIALS: gov identifier: NCT05579119.

DPP-4 inhibitor sitagliptin treatment results in altered myocardial metabolic proteome and oxidative phosphorylation in a swine model of chronic myocardial ischemia.

Small animal models have shown improved cardiac function with DPP-4 inhibition, but many human studies have shown worse outcomes or no benefit. We seek to bridge the gap by studying the DPP-4 inhibitor sitagliptin in a swine model of chronic myocardial ischemia using proteomic analysis. Thirteen Yorkshire swine underwent the placement of an ameroid constrictor on the left coronary circumflex artery to model chronic myocardial ischemia. Two weeks post-op, swine received either sitagliptin 100 mg daily (SIT, n = 5) or no drug (CON, n = 8). After 5 weeks of treatment, swine underwent functional measurements and tissue harvest. In the SIT group compared to CON, there was a trend towards decreased cardiac index (p = 0.06). The non-ischemic and ischemic myocardium had 396 and 166 significantly decreased proteins, respectively, in the SIT group compared to CON (all p < 0.01). This included proteins involved in fatty acid oxidation (FAO), myocardial contraction, and oxidative phosphorylation (OXPHOS). Sitagliptin treatment resulted in a trend towards decreased cardiac index and decreased expression of proteins involved in OXPHOS, FAO, and myocardial contraction in both ischemic and non-ischemic swine myocardium. These metabolic and functional changes may provide some mechanistic evidence for outcomes seen in clinical studies.

Safety, tolerability, pharmacokinetics and pharmacokinetic-pharmacodynamic modeling of cetagliptin in patients with type 2 diabetes mellitus.

Aims: To evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of cetagliptin (CAS number:2243737-33-7) in Chinese patients with type 2 diabetes mellitus (T2DM). A population PK/PD model was developed to quantify the PK and PD characteristics of cetagliptin in patients. Materials and methods: 32 Chinese adults with T2DM were enrolled in this study. The subjects were randomly assigned to receive either cetagliptin (50 mg or 100 mg), placebo, or sitagliptin (100 mg) once daily for 14 days. Blood samples were collected for PK and PD analysis. Effects on glucose, insulin, C-peptide, and glucagon were evaluated following an oral glucose tolerance test (OGTT) (day15). Effects on HbA1c and glycated albumin (GA), and safety assessments were also conducted. Meanwhile, a population PK/PD model was developed by a sequential two-step analysis approach using Phoenix. Results: Following multiple oral doses, cetagliptin was rapidly absorbed and the mean half-life were 34.9-41.9 h. Steady-state conditions were achieved after 1 week of daily dosing and the accumulation was modest. The intensity and duration of DPP-4 inhibition induced by 50 mg cetagliptin were comparable with those induced by sitagliptin, and 100 mg cetagliptin showed a much longer sustained DPP-4 inhibition (≥80%) than sitagliptin. Compared with placebo group, plasma active GLP-1 AUEC0-24h increased by 2.20- and 3.36-fold in the 50 mg and 100 mg cetagliptin groups. A decrease of plasma glucose and increase of insulin and C-peptide were observed following OGTT in cetagliptin groups. Meanwhile, a tendency of reduced GA was observed, whereas no decreasing trend was observed in HbA1c. All adverse events related to cetagliptin and sitagliptin were assessed as mild. A population PK/PD model was successfully established. The two-compartment model and Sigmoid-Emax model could fit the observed data well. Total bilirubin (TBIL) was a covariate of volume of peripheral compartment distribution (V2), and V2 increased with the increase of TBIL. Conclusions: Cetagliptin was well tolerated, inhibited plasma DPP-4 activity, increased plasma active GLP-1 levels, and exhibited a certain trend of glucose-lowering effect in patients with T2DM. The established population PK/PD model adequately described the PK and PD characteristics of cetagliptin.

Network-based screening identifies sitagliptin as an antitumor drug targeting dendritic cells.

BACKGROUND: Dendritic cell (DC)-mediated antigen presentation is essential for the priming and activation of tumor-specific T cells. However, few drugs that specifically manipulate DC functions are available. The identification of drugs targeting DC holds great promise for cancer immunotherapy. METHODS: We observed that type 1 conventional DCs (cDC1s) initiated a distinct transcriptional program during antigen presentation. We used a network-based approach to screen for cDC1-targeting therapeutics. The antitumor potency and underlying mechanisms of the candidate drug were investigated in vitro and in vivo. RESULTS: Sitagliptin, an oral gliptin widely used for type 2 diabetes, was identified as a drug that targets DCs. In mouse models, sitagliptin inhibited tumor growth by enhancing cDC1-mediated antigen presentation, leading to better T-cell activation. Mechanistically, inhibition of dipeptidyl peptidase 4 (DPP4) by sitagliptin prevented the truncation and degradation of chemokines/cytokines that are important for DC activation. Sitagliptin enhanced cancer immunotherapy by facilitating the priming of antigen-specific T cells by DCs. In humans, the use of sitagliptin correlated with a lower risk of tumor recurrence in patients with colorectal cancer undergoing curative surgery. CONCLUSIONS: Our findings indicate that sitagliptin-mediated DPP4 inhibition promotes antitumor immune response by augmenting cDC1 functions. These data suggest that sitagliptin can be repurposed as an antitumor drug targeting DC, which provides a potential strategy for cancer immunotherapy.

Differential Effects of Type 2 Diabetes Treatment Regimens on Diabetes Distress and Depressive Symptoms in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE).

OBJECTIVE: We evaluated whether adding basal insulin to metformin in adults with early type 2 diabetes mellitus (T2DM) would increase emotional distress relative to other treatments. RESEARCH DESIGN AND METHODS: The Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) of adults with T2DM of <10 years' duration, HbA1c 6.8-8.5%, and taking metformin monotherapy randomly assigned participants to add insulin glargine U-100, sulfonylurea glimepiride, the glucagon-like peptide-1 receptor agonist liraglutide, or the dipeptidyl peptidase 4 inhibitor sitagliptin. The Emotional Distress Substudy enrolled 1,739 GRADE participants (mean [SD] age 58.0 [10.2] years, 32% female, 56% non-Hispanic White, 18% non-Hispanic Black, 17% Hispanic) and assessed diabetes distress and depressive symptoms every 6 months. Analyses examined differences at 1 year and over the 3-year follow-up. RESULTS: Across treatments, diabetes distress (-0.24, P < 0.0001) and depressive symptoms (-0.67, P < 0.0001) decreased over 1 year. Diabetes distress was lower at 1 year for the glargine group than for the other groups combined (-0.10, P = 0.002). Diabetes distress was also lower for liraglutide than for glimepiride or sitagliptin (-0.10, P = 0.008). Over the 3-year follow-up, there were no significant group differences in total diabetes distress; interpersonal diabetes distress remained lower for those assigned to liraglutide. No significant differences were observed for depressive symptoms. CONCLUSIONS: Contrary to expectations, this randomized trial found no evidence for a deleterious effect of basal insulin on emotional distress. Glargine lowered diabetes distress modestly at 1 year rather than increasing it. Liraglutide also reduced diabetes distress at 1 year. Results can inform treatment decisions for adults with early T2DM.

Cardiovascular Outcomes in GRADE (Glycemia Reduction Approaches in Type 2 Diabetes: A Comparative Effectiveness Study).

BACKGROUND: Cardiovascular disease is a major cause of morbidity and mortality in patients with type 2 diabetes. The effects of glucose-lowering medications on cardiovascular outcomes in individuals with type 2 diabetes and low cardiovascular risk are unclear. We investigated cardiovascular outcomes by treatment group in participants randomly assigned to insulin glargine, glimepiride, liraglutide, or sitagliptin, added to baseline metformin, in GRADE (Glycemia Reduction Approaches in Type 2 Diabetes: A Comparative Effectiveness Study). METHODS: A total of 5047 participants with a mean±SD age of 57.2±10.0 years, type 2 diabetes duration of 4.0±2.7 years, and low baseline prevalence of cardiovascular disease (myocardial infarction, 5.1%; cerebrovascular accident, 2.0%) were followed for a median of 5 years. Prespecified outcomes included between-group time-to-first event analyses of MACE-3 (composite of major adverse cardiovascular events: cardiovascular death, myocardial infarction, and stroke), MACE-4 (MACE-3+unstable angina requiring hospitalization or revascularization), MACE-5 (MACE-4+coronary revascularization), MACE-6 (MACE-5+hospitalization for heart failure), and the individual components. MACE outcomes and hospitalization for heart failure in the liraglutide-treated group were compared with the other groups combined using Cox proportional hazards models. MACE-6 was also analyzed as recurrent events using a proportional rate model to compare all treatment groups. RESULTS: We observed no statistically significant differences in the cumulative incidence of first MACE-3, MACE-4, MACE-5, or MACE-6, or their individual components, by randomized treatment group. However, when compared with the other treatment groups combined, the liraglutide-treated group had a significantly lower risk of MACE-5 (adjusted hazard ratio, 0.70 [95% CI, 0.54-0.91]; P=0.021), MACE-6 (adjusted hazard ratio, 0.70 [95% CI, 0.55-0.90]; P=0.021), and hospitalization for heart failure (adjusted hazard ratio, 0.49 [95% CI, 0.28-0.86]; P=0.022). Compared with the liraglutide group, significantly higher rates of recurrent MACE-6 events occurred in the groups treated with glimepiride (rate ratio, 1.61 [95% CI, 1.13-2.29]) or sitagliptin (rate ratio 1.75; [95% CI, 1.24-2.48]). CONCLUSIONS: This comparative effectiveness study of a contemporary cohort of adults with type 2 diabetes, largely without established cardiovascular disease, suggests that liraglutide treatment may reduce the risk of cardiovascular events in patients at relatively low risk compared with other commonly used glucose-lowering medications. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01794143.

Impact of Insulin Sensitivity and ß-Cell Function Over Time on Glycemic Outcomes in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE): Differential Treatment Effects of Dual Therapy.

OBJECTIVE: To compare the effects of insulin sensitivity and ß-cell function over time on HbA1c and durability of glycemic control in response to dual therapy. RESEARCH DESIGN AND METHODS: GRADE participants were randomized to glimepiride (n = 1,254), liraglutide (n = 1,262), or sitagliptin (n = 1,268) added to baseline metformin and followed for mean ± SD 5.0 ± 1.3 years, with HbA1c assessed quarterly and oral glucose tolerance tests at baseline, 1, 3, and 5 years. We related time-varying insulin sensitivity (HOMA 2 of insulin sensitivity [HOMA2-%S]) and early (0-30 min) and total (0-120 min) C-peptide (CP) responses to changes in HbA1c and glycemic failure (primary outcome HbA1c ≥7% [53 mmol/mol] and secondary outcome HbA1c >7.5% [58 mmol/mol]) and examined differential treatment responses. RESULTS: Higher HOMA2-%S was associated with greater initial HbA1c lowering (3 months) but not subsequent HbA1c rise. Greater CP responses were associated with a greater initial treatment response and slower subsequent HbA1c rise. Higher HOMA2-%S and CP responses were each associated with lower risk of primary and secondary outcomes. These associations differed by treatment. In the sitagliptin group, HOMA2-%S and CP responses had greater impact on initial HbA1c reduction (test of heterogeneity, P = 0.009 HOMA2-%S, P = 0.018 early CP, P = 0.001 total CP) and risk of primary outcome (P = 0.005 HOMA2-%S, P = 0.11 early CP, P = 0.025 total CP) but lesser impact on HbA1c rise (P = 0.175 HOMA2-%S, P = 0.006 early CP, P < 0.001 total CP) in comparisons with the glimepiride and liraglutide groups. There were no differential treatment effects on secondary outcome. CONCLUSIONS: Insulin sensitivity and ß-cell function affected treatment outcomes irrespective of drug assignment, with greater impact in the sitagliptin group on initial (short-term) HbA1c response in comparison with the glimepiride and liraglutide groups.

Comparative Effects of Randomized Second-line Therapy for Type 2 Diabetes on a Composite Outcome Incorporating Glycemic Control, Body Weight, and Hypoglycemia: An Analysis of the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE).

OBJECTIVE: In Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) (5,047 participants, mean follow-up 5.0 years), differences in glycemic control were demonstrated over time among four randomized therapies added to metformin. Weight gain and hypoglycemia are also important outcomes for people with type 2 diabetes. We compared the effects of the four randomized GRADE medications on a composite outcome incorporating glycemic deterioration, weight gain, and hypoglycemia. RESEARCH DESIGN AND METHODS: The composite outcome was time to first occurrence of any of the following: HbA1c >7.5%, confirmed; ≥5% weight gain; or severe or recurrent nonsevere hypoglycemia. Secondary analyses included examination of individual components of the composite outcome, subgroup effects and potential mediators, and treatment satisfaction. Cumulative incidence was estimated with the Kaplan-Meier estimator. Cox proportional hazards models were used to assess pairwise group differences in risk of an outcome. RESULTS: Risk of reaching the composite outcome (events per 100 participants per treatment year [PTYs]) was lowest with liraglutide (19 per 100 PTYs) followed by sitagliptin (26 per 100 PTYs), glargine (29 per 100 PTYs), and glimepiride (40 per 100 PTYs); all pairwise comparisons were statistically significant. The order was the same for risk of weight gain and hypoglycemia, but risk of glycemic deterioration was lowest with glargine, followed by liraglutide, glimepiride, and sitagliptin. No significant heterogeneity in risk of composite outcome was detected across prespecified covariates. Participants who reached the composite outcome had modestly but significantly lower treatment satisfaction. CONCLUSIONS: Among participants treated with common second-line drug classes for type 2 diabetes, the liraglutide group had the lowest and glimepiride the highest risk of reaching a composite outcome encompassing glycemic deterioration, weight gain, and hypoglycemia. These findings may inform decision-making regarding type 2 diabetes therapy.

Low-Dose Sulfonylurea Plus DPP4 Inhibitor Lower Blood Glucose and Enhance Beta-Cell Function Without Hypoglycemia.

CONTEXT: Low-dose sulfonylureas (SUs) have been found to augment the classical incretin effect, increase glucose sensitivity and late phase incretin potentiation. OBJECTIVE: To evaluate potential synergy between low-dose SU plus a dipeptidyl peptidase 4 (DPP4) inhibitor. METHODS: Unblinded randomized crossover study at the Clinical Research Centre, University of Dundee. Thirty participants with T2DM (HbA1c < 64 mmol/mol) were treated with diet or metformin. Participants completed 4, 14-day blocks in a random order: control, gliclazide 20 mg (SU), sitagliptin 100 mg (DPP4 inhibitor [DPP4i]), or combination (SUDPP4i). A mixed meal test was conducted after each intervention. The primary outcome was the effect of treatment on beta-cell glucose sensitivity. Secondary outcomes included frequency of glucose <3 mmol/L on continuous glucose monitoring, subanalyses by genotype (KNCJ11 E23K), gender, and body mass index. RESULTS: SU combination with DPP4i showed additive effect on glucose lowering: mean glucose area under the curve (mean 95% CI) (mmol/L) was control 11.5 (10.7-12.3), DPP4i 10.2 (9.4-11.1), SU 9.7 (8.9-10.5), SUDPP4i 8.7 (7.9-9.5) (P < .001). Glucose sensitivity mirrored the additive effect (pmol min-1 m-2 mM-1): control 71.5 (51.1-91.9), DPP4i 75.9 (55.7-96.0), SU 86.3 (66.1-106.4), SUDPP4i 94.1 (73.9-114.3) (P = .04). The additive effect was seen in men but not women. Glucose time in range <3 mmol/L on continuous glucose monitoring (%) was unaffected: control 1 (2-4), DPP4i 2 (3-6), SU 1 (0-4), SUDPP4i 3 (2-7) (P = .65). CONCLUSION: Low-dose sulfonylurea plus DPP4i has a potent glucose-lowering effect through augmentation of beta-cell function. A double-blind randomized controlled trial would formalize efficacy and safety of this combination, which may avoid negative aspects of SU.

Longitudinal Effects of Glucose-Lowering Medications on ß-Cell Responses and Insulin Sensitivity in Type 2 Diabetes: The GRADE Randomized Clinical Trial.

OBJECTIVE: To compare the long-term effects of glucose-lowering medications (insulin glargine U-100, glimepiride, liraglutide, and sitagliptin) when added to metformin on insulin sensitivity and ß-cell function. RESEARCH DESIGN AND METHODS: In the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) cohort with type 2 diabetes (n = 4,801), HOMA2 was used to estimate insulin sensitivity (HOMA2-%S) and fasting ß-cell function (HOMA2-%B) at baseline and 1, 3, and 5 years on treatment. Oral glucose tolerance test ß-cell responses (C-peptide index [CPI] and total C-peptide response [incremental C-peptide/incremental glucose over 120 min]) were evaluated at the same time points. These responses adjusted for HOMA2-%S in regression analysis provided estimates of ß-cell function. RESULTS: HOMA2-%S increased from baseline to year 1 with glargine and remained stable thereafter, while it did not change from baseline in the other treatment groups. HOMA2-%B and C-peptide responses were increased to variable degrees at year 1 in all groups but then declined progressively over time. At year 5, CPI was similar between liraglutide and sitagliptin, and higher for both than for glargine and glimepiride [0.80, 0.87, 0.74, and 0.64 (nmol/L)/(mg/dL) * 100, respectively; P < 0.001], while the total C-peptide response was greatest with liraglutide, followed in descending order by sitagliptin, glargine, and glimepiride [1.54, 1.25, 1.02, and 0.87 (nmol/L)/(mg/dL) * 100, respectively, P < 0.001]. After adjustment for HOMA2-%S to obtain an estimate of ß-cell function, the nature of the change in ß-cell responses reflected those in ß-cell function. CONCLUSIONS: The differential long-term effects on insulin sensitivity and ß-cell function of four different glucose-lowering medications when added to metformin highlight the importance of the loss of ß-cell function in the progression of type 2 diabetes.

Preclinical Repurposing of Sitagliptin as a Drug Candidate for Colorectal Cancer by Targeting CD24/CTNNB1/SOX4-Centered Signaling Hub.

Despite significant advances in treatment modalities, colorectal cancer (CRC) remains a poorly understood and highly lethal malignancy worldwide. Cancer stem cells (CSCs) and the tumor microenvironment (TME) have been shown to play critical roles in initiating and promoting CRC progression, metastasis, and treatment resistance. Therefore, a better understanding of the underlying mechanisms contributing to the generation and maintenance of CSCs is crucial to developing CSC-specific therapeutics and improving the current standard of care for CRC patients. To this end, we used a bioinformatics approach to identify increased CD24/SOX4 expression in CRC samples associated with poor prognosis. We also discovered a novel population of tumor-infiltrating CD24+ cancer-associated fibroblasts (CAFs), suggesting that the CD24/SOX4-centered signaling hub could be a potential therapeutic target. Pathway networking analysis revealed a connection between the CD24/SOX4-centered signaling, ß-catenin, and DPP4. Emerging evidence indicates that DPP4 plays a role in CRC initiation and progression, implicating its involvement in generating CSCs. Based on these bioinformatics data, we investigated whether sitagliptin, a DPP4 inhibitor and diabetic drug, could be repurposed to inhibit colon CSCs. Using a molecular docking approach, we demonstrated that sitagliptin targeted CD24/SOX4-centered signaling molecules with high affinity. In vitro experimental data showed that sitagliptin treatment suppressed CRC tumorigenic properties and worked in synergy with 5FU and this study thus provided preclinical evidence to support the alternative use of sitagliptin for treating CRC.

Serum thrombospondin-2 level changes with liver stiffness improvement in patients with type 2 diabetes.

OBJECTIVE: Baseline circulating thrombospondin-2 (TSP2) level was identified as a potential novel hepatic fibrosis biomarker that associates with development and progression of hepatic fibrosis in patients with nonalcoholic fatty liver disease and type 2 diabetes. Here, we investigated whether circulating TSP2 levels changed with improvement in liver stiffness (LS), which reflects liver fibrosis on transient elastography. DESIGN: Serum TSP2 levels were measured in participants from a randomized, open-label intervention study, at baseline and after 24-weeks treatment of either dapagliflozin 10 mg (N = 30) or sitagliptin 100 mg daily (N = 30). Vibration-controlled transient elastography was performed to evaluate the severity of hepatic fibrosis and steatosis using LS and controlled attenuation parameter (CAP), respectively. PATIENTS AND MEASUREMENTS: Among all 60 participants with similar clinical characteristics at baseline (mean HbA1c 8.9%, CAP 289 dB/m and LS 5.8 kPa), despite similar HbA1c lowering, treatment with dapagliflozin, but not sitagliptin, led to significant improvements in body weight (BW) (p = .012), CAP (p = .015) and LS (p = .011) after 24 weeks. RESULTS: Serum TSP2 level decreased significantly from baseline in dapagliflozin-treated participants (p = .035), whereas no significant change was observed with sitagliptin. In correlation analysis, change in serum TSP2 levels only positively correlated with change in LS (r = .487, p = .006), but not with changes in BW, CAP or HbA1c after dapagliflozin treatment. CONCLUSIONS: Serum TSP2 level decreased with LS after dapagliflozin treatment, and was independent of improvements in BW, glycemic control and hepatic steatosis, further supporting the potential of serum TSP2 level as a novel hepatic fibrosis biomarker in type 2 diabetes.