Type 2 Diabetes Mellitus Trials Research Articles

SGLT-2 Inhibitor Use in Heart Failure: A Review for Nurses.

Sodium-glucose cotransporter-2 (SGLT-2) inhibitors (empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin) are a new class of heart failure medications that have previously been exclusively utilized in the management of type 2 diabetes mellitus (T2DM). The rationale for using SGLT-2 inhibitors in patients with heart failure has stemmed from recent landmark clinical trials in T2DM in which reductions in mortality and hospitalization for heart failure were first observed. On the basis of these robust outcomes, empagliflozin has further been evaluated in heart failure with reduced ejection fraction (HFrEF) and preserved ejection fraction and dapagliflozin solely in the management of HFrEF. While cardiovascular outcomes among each agent vary depending on the patient population, updates among both the American and European guidelines have included SGLT-2 inhibitors as pillars of therapy. The exact mechanisms for how SGLT-2 inhibitors are beneficial in heart failure are unknown, but current hypotheses include multiple metabolic and hemodynamic mechanisms. The purpose of this review is to summarize available literature focusing on the use of the SGLT-2 inhibitors as adjunctive therapy in heart failure, as well as evaluate mechanisms for heart failure benefit, adverse effects, and practical considerations for using these agents in the clinical setting.

A Framework for Systematic Assessment of Clinical Trial Population Representativeness Using Electronic Health Records Data.

Clinical trials are the gold standard for generating robust medical evidence, but clinical trial results often raise generalizability concerns, which can be attributed to the lack of population representativeness. The electronic health records (EHRs) data are useful for estimating the population representativeness of clinical trial study population. This research aims to estimate the population representativeness of clinical trials systematically using EHR data during the early design stage. We present an end-to-end analytical framework for transforming free-text clinical trial eligibility criteria into executable database queries conformant with the Observational Medical Outcomes Partnership Common Data Model and for systematically quantifying the population representativeness for each clinical trial. We calculated the population representativeness of 782 novel coronavirus disease 2019 (COVID-19) trials and 3,827 type 2 diabetes mellitus (T2DM) trials in the United States respectively using this framework. With the use of overly restrictive eligibility criteria, 85.7% of the COVID-19 trials and 30.1% of T2DM trials had poor population representativeness. This research demonstrates the potential of using the EHR data to assess the clinical trials population representativeness, providing data-driven metrics to inform the selection and optimization of eligibility criteria.

32 Quantifying the Prevalence of Frailty in Drug Trials and the Relationship with Serious Adverse Events

Abstract Introduction Frailty is common in clinical practice, but trials rarely report on participant frailty. Consequently, clinicians and guideline-developers assume frailty is largely absent from trials and have questioned the relevance of trial findings to frail people. Therefore, we examined frailty in phase 3/4 industry-sponsored clinical trials of pharmacological interventions for three exemplar conditions: type 2 diabetes mellitus (T2DM), rheumatoid arthritis (RA), and chronic obstructive pulmonary disease (COPD). Methods We constructed a 40-item frailty index (FI) in 19 clinical trials (7 T2DM, 8 RA, 4 COPD, mean age 42–65 years) using individual-level participant data. Participants with a FI >0.24 were considered “frail”. Baseline disease severity was assessed using HbA1c for T2DM, Disease Activity Score-28 (DAS28) for RA, and % predicted FEV1 for COPD. Using generalised gamma regression, we modelled FI on age, sex and disease severity. In negative binomial regression we modelled serious adverse event rates on FI, and combined results for each index condition in a random-effects meta-analysis. Results All trials included frail participants: prevalence 7–21% in T2DM trials, 33–73% in RA trials, and 15–22% in COPD trials. Increased disease severity and female sex were associated with higher FI in all trials. Frailty was associated with age in T2DM and RA trials, but not in COPD. Across all trials, and after adjusting for age, sex, and disease severity, higher FI predicted increased risk of serious adverse events; the pooled incidence rate ratios (per 0.1-point increase in FI scale) were 1.46 (95% CI 1.21–1.75), 1.45 (1.13–1.87) and 1.99 (1.43–2.76) for T2DM, RA and COPD, respectively. Conclusion Frailty is identifiable and prevalent among middle aged and older participants in phase 3/4 drug trials and has clinically important safety implications. Trial data may be harnessed to better understand chronic disease management in people living with frailty.

Gender disparities in coronavirus disease 2019 clinical trial leadership

ObjectivesTo compare the gender distribution of clinical trial leadership in coronavirus disease 2019 (COVID-19) clinical trials. MethodsWe searched https://clinicaltrials.gov/ and retrieved all clinical trials on COVID-19 from 1 January 2020 to 26 June 2020. As a comparator group, we have chosen two fields that are not related to emerging infections and infectious diseases: and considered not directly affected by the pandemic: breast cancer and type 2 diabetes mellitus (T2DM) and included studies within the aforementioned study period as well as those registered in the preceding year (pre-study period: 1 January 2019 to 31 December 2019). Gender of the investigator was predicted using the genderize.io application programming interface. The repository of the data sets used to collect and analyse the data are available at https://osf.io/k2r57/. ResultsOnly 27.8% (430/1548) of principal investigators among COVID-19-related studies were women, which is significantly different compared with 54.9% (156/284) and 42.1% (56/133) for breast cancer (p < 0.005) and T2DM (p < 0.005) trials over the same period, respectively. During the pre-study period, the proportion of principal investigators who were predicted to be women were 49.7% (245/493) and 44.4% (148/333) for breast cancer and T2DM trials, respectively, and the difference was not statistically significant when compared with results from the study period (p > 0.05). ConclusionWe demonstrate that less than one-third of COVID-19-related clinical trials are led by women, half the proportion observed in non-COVID-19 trials over the same period, which remained similar to the pre-study period. These gender disparities during the pandemic may not only indicate a lack of female leadership in international clinical trials and involvement in new projects but also reveal imbalances in women's access to research activities and funding during health emergencies.

Identifying frailty in trials: an analysis of individual participant data from trials of novel pharmacological interventions

BackgroundFrailty is common in clinical practice, but trials rarely report on participant frailty. Consequently, clinicians and guideline-developers assume frailty is largely absent from trials and have questioned the relevance of trial findings to frail people. Therefore, we examined frailty in phase 3/4 industry-sponsored clinical trials of pharmacological interventions for three exemplar conditions: type 2 diabetes mellitus (T2DM), rheumatoid arthritis (RA), and chronic obstructive pulmonary disease (COPD).MethodsWe constructed a 40-item frailty index (FI) in 19 clinical trials (7 T2DM, 8 RA, 4 COPD, mean age 42–65 years) using individual-level participant data. Participants with a FI > 0.24 were considered ‘frail’. Baseline disease severity was assessed using HbA1c for T2DM, Disease Activity Score-28 (DAS28) for RA, and % predicted FEV1 for COPD. Using generalised gamma regression, we modelled FI on age, sex, and disease severity. In negative binomial regression, we modelled serious adverse event rates on FI and combined results for each index condition in a random-effects meta-analysis.ResultsAll trials included frail participants: prevalence 7–21% in T2DM trials, 33–73% in RA trials, and 15–22% in COPD trials. The 99th centile of the FI ranged between 0.35 and 0.45. Female sex was associated with higher FI in all trials. Increased disease severity was associated with higher FI in RA and COPD, but not T2DM. Frailty was associated with age in T2DM and RA trials, but not in COPD. Across all trials, and after adjusting for age, sex, and disease severity, higher FI predicted increased risk of serious adverse events; the pooled incidence rate ratios (per 0.1-point increase in FI scale) were 1.46 (95% CI 1.21–1.75), 1.45 (1.13–1.87), and 1.99 (1.43–2.76) for T2DM, RA, and COPD, respectively.ConclusionThe upper limit of frailty in trials is lower than has been described in the general population. However, mild to moderate frailty was common, suggesting trial data may be harnessed to inform disease management in people living with frailty. Participants with higher FI experienced more serious adverse events, suggesting screening for frailty in trial participants would enable identification of those that merit closer monitoring. Frailty is identifiable and prevalent among middle-aged and older participants in phase 3/4 drug trials and has clinically important safety implications.

The trials and tribulations of determining HbA1c targets for diabetes mellitus.

Glycated haemoglobin (HbA1c) is considered the gold standard for predicting glycaemia-associated risks for the microvascular and macrovascular complications of diabetes mellitus over 5-10 years. The value of HbA1c in the care of patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) is unassailable, yet HbA1c targets remain contentious. Guidelines from diabetes care organizations recommend conflicting HbA1c targets - generally between 6.5% and 8%. However, all such organizations advocate for individualization of HbA1c targets, leaving both health-care providers and their patients confused about what HbA1c target is appropriate in an individual patient. In this Review, we outline the landmark T1DM and T2DM trials that informed the current guidelines, we discuss the evidence that drives individualized HbA1c targets, we examine the limitations of HbA1c, and we consider alternatives for monitoring glycaemic control. Ultimately, in synthesizing this literature, we argue for an HbA1c target of <7% for most individuals, but emphasize the importance of helping patients determine their own personal goals and determinants of quality of life that are independent of a particular glycaemic target. We also recognize that as newer technologies and anti-hyperglycaemic therapies emerge, glycaemic targets will continue to evolve.

Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist.

Tirzepatide (LY3298176) is a dual GIP and GLP-1 receptor agonist under development for the treatment of type 2 diabetes mellitus (T2DM), obesity, and nonalcoholic steatohepatitis. Early phase trials in T2DM indicate that tirzepatide improves clinical outcomes beyond those achieved by a selective GLP-1 receptor agonist. Therefore, we hypothesized that the integrated potency and signaling properties of tirzepatide provide a unique pharmacological profile tailored for improving broad metabolic control. Here, we establish methodology for calculating occupancy of each receptor for clinically efficacious doses of the drug. This analysis reveals a greater degree of engagement of tirzepatide for the GIP receptor than the GLP-1 receptor, corroborating an imbalanced mechanism of action. Pharmacologically, signaling studies demonstrate that tirzepatide mimics the actions of native GIP at the GIP receptor but shows bias at the GLP-1 receptor to favor cAMP generation over β-arrestin recruitment, coincident with a weaker ability to drive GLP-1 receptor internalization compared with GLP-1. Experiments in primary islets reveal β-arrestin1 limits the insulin response to GLP-1, but not GIP or tirzepatide, suggesting that the biased agonism of tirzepatide enhances insulin secretion. Imbalance toward GIP receptor, combined with distinct signaling properties at the GLP-1 receptor, together may account for the promising efficacy of this investigational agent.

The effect of luseogliflozin on bone microarchitecture in older patients with type 2 diabetes: study protocol for a randomized controlled pilot trial using second-generation, high-resolution, peripheral quantitative computed tomography (HR-pQCT)

BackgroundOlder patients with type 2 diabetes mellitus (T2DM) have an increased risk of bone fracture independent of their bone mineral density (BMD), which is explained mainly by the deteriorated bone quality in T2DM compared to that in non-diabetic adults. Sodium-glucose co-transporter (SGLT) 2 inhibitors have been studied in several trials in T2DM, and the Canagliflozin Cardiovascular Assessment Study showed an increased fracture risk related to treatment with the SGLT2 inhibitor canagliflozin, although no evidence of increased fracture risk with treatment with other SGLT2 inhibitors has been reported. The mechanism of the difference in the fracture risk between the SGLT2 inhibitors is unknown, but the differences among the SGLT2 inhibitors in the selectivity of SGLT2 against SGLT1 may affect bone metabolism, since among the SGLT2 inhibitors the selectivity of canagliflozin is lowest. We will investigate whether the SGLT2 inhibitor luseogliflozin, which has the higher SGLT2 selectivity, affects bone metabolism by using high-resolution, peripheral quantitative computed tomography (HR-pQCT) which provides direct in vivo morphometric information about the bone microarchitecture.Methods/designThis is a single-center, randomized, open-label, active-controlled, parallel pilot trial. Eligible participants are older (age ≥ 60 years) individuals with T2DM with HbA1c levels at 7.0–8.9%. A total of 24 participants will be allocated to either the luseogliflozin group (taking luseogliflozin) or the control group (taking metformin) in a 1:1 ratio to compare the groups’ changes in bone microarchitecture of the radius and tibia which are analyzed by HR-pQCT before and at 48 weeks after the administration of each medication. The laboratory data associated with glycemic control and bone metabolism will be collected every 12 weeks during the study. Recruitment began in June 2019.DiscussionThe reason that we use metformin as an active control is to avoid yielding differences in glycemic control between the luseogliflozin and control groups. Besides, metformin is considered to have a neutral effect on bone. This trial should reveal the effect of luseogliflozin on bone metabolism in older patients with T2DM.Trial registrationThe study was registered with the University Hospital Medical Information Network (UMIN000036202) on 1 April 2019 and with the Japan Registry of Clinicla Trials (jRCTs071180061) on 14 March 2019.

A Prediction Model for Identifying Type 2 Diabetics at Highest Risk of Cardiorenal Outcomes

Background Type 2 diabetes mellitus (T2DM) affects around 10% of the US adult population and associates with high levels of cardiovascular (CV) and renal morbidity and mortality. Recent randomized clinical trials in T2DM have shown cardiorenal benefits with novel antidiabetic therapies. Real world utilization of these therapies may be maximally cost-effective when targeted to those at highest risk of cardiorenal outcomes. Accordingly, this study created a risk prediction model for a composite cardiorenal endpoint of CV death, hospitalization for heart failure (HHF), and end stage renal disease (ESRD) in T2DM patients and proposes a quantitative risk threshold for labeling patients as being at high risk of this outcome. Methods This retrospective cohort study included patients with pre-existing or newly diagnosed T2DM drawn from the electronic medical record (EMR) of a single, large integrated health care system. Candidate predictors for prediction model development were determined from EMR documentation in the two years prior to a baseline office visit. A time-to-first-event variable was created for the composite endpoint of CV death, HHF, and ESRD, and significant predictors determined using Cox regression. “High risk” patients were defined as the 10% highest risk patients according to prediction model output. Results Among 57,646 T2DM patients, 8505 (15%) experienced an event over a mean follow-up of 6.9 years. CV death was the most frequent outcome (53% of first events), followed by HHF (25%) and ESRD (22%). The strongest predictors of the composite outcome were age, blood urea nitrogen, coronary artery disease, HF, and atrial fibrillation. The final proposed 19-predictor model had a c-statistic of 0.792. The 10% highest risk patients (“high risk”) according to prediction model variables had estimated event rates >5%, >15%, and >30% at 1, 3, and 5 years after the baseline date. Conclusions T2DM patients have a high rate of CV and renal outcomes, and recent clinical trial evidence shows novel antidiabetic therapies reduce these outcomes. Patients at highest risk for these outcomes are expected to receive the greatest event rate reduction from these novel therapies.

Efficacies of stem cell therapies for functional improvement of the β cell in patients with diabetes: A systematic review of controlled clinical trials.

Background & Aim This study was performed to investigate whether stem cell therapy enhances β cell function by meta-analysis with proper consideration of variability of outcome measurements in controlled trial of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) patients. Methods, Results & Conclusion Method A systematic search was performed from inception to January 2018 in PubMed, EMBASE, and Cochrane databases. Β cell function was assessed by stimulated C-peptide, fasting C-peptide, normal glycosylated hemoglobin levels (HbA1C), and exogenous insulin dose patterns. The quality of the studies were assessed by both the Cochrane Collaboration's Risk of Bias (ROB) for Randomized controlled trials and the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) for non-randomized controlled trials. Result From the selected final 15 articles, total of 16 trials were analyzed. There were 6 T1DM trials (total 153 cases) and 10 T2DM trials (total 457 cases). In T2DM patients, the changes in stimulated C-peptide, HbA1c, and exogenous insulin dose versus baseline showed a favorable pattern with significant heterogeneity in stem cell therapy. In T1DM, there was no significant difference between control group and stem cell therapy group in three indicators except for HbA1c. Most of the studies were rated as having high risk of bias in the quality assessment. Conclusion The stem cell therapy for DM patients is not effective in T1 DM but seems to be effective in improving the β cell function in T2 DM. Further verification through a rigorously designed study is warranted.

Efficacies of Stem Cell Therapies for Functional Improvement of the β Cell in Patients with Diabetes: A Systematic Review of Controlled Clinical Trials.

Background and ObjectivesThis study was performed to investigate whether stem cell therapy enhances β cell function by meta-analysis with proper consideration of variability of outcome measurements in controlled trial of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) patients.MethodsA systematic search was performed from inception to January 2018 in PubMed, EMBASE, and Cochrane databases. β cell function was assessed by stimulated C-peptide, fasting C-peptide, normal glycosylated hemoglobin levels (HbA1C), and exogenous insulin dose patterns. The quality of the studies were assessed by both the Cochrane Collaboration’s Risk of Bias (ROB) for Randomized controlled trials and the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) for non-randomized controlled trials.ResultsFrom the selected final 15 articles, total of 16 trials were analyzed. There were 6 T1DM trials (total 153 cases) and 10 T2DM trials (total 457 cases). In T2DM patients, the changes in stimulated C-peptide, HbA1c, and exogenous insulin dose versus baseline showed a favorable pattern with a significant heterogeneity in stem cell therapy. In T1DM, there was no significant difference between control group and stem cell therapy group in three indicators except for HbA1c. Most of the studies were rated as having high risk of bias in the quality assessment.ConclusionsThe stem cell therapy for DM patients is not effective in T1DM but seems to be effective in improving the β cell function in T2DM. However the observed effect should be interpreted with caution due to the significant heterogeneity and high risk of bias within the studies. Further verification through a rigorously designed study is warranted.

Validation of the Economic and Health Outcomes Model of Type 2 Diabetes Mellitus (ECHO-T2DM).

The Economic and Health Outcomes Model of Type 2 Diabetes Mellitus (ECHO-T2DM) was developed to address study questions pertaining to the cost-effectiveness of treatment alternatives in the care of patients with type 2 diabetes mellitus (T2DM). Naturally, the usefulness of a model is determined by the accuracy of its predictions. A previous version of ECHO-T2DM was validated against actual trial outcomes and the model predictions were generally accurate. However, there have been recent upgrades to the model, which modify model predictions and necessitate an update of the validation exercises. The objectives of this study were to extend the methods available for evaluating model validity, to conduct a formal model validation of ECHO-T2DM (version 2.3.0) in accordance with the principles espoused by the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) and the Society for Medical Decision Making (SMDM), and secondarily to evaluate the relative accuracy of four sets of macrovascular risk equations included in ECHO-T2DM. We followed the ISPOR/SMDM guidelines on model validation, evaluating face validity, verification, cross-validation, and external validation. Model verification involved 297 'stress tests', in which specific model inputs were modified systematically to ascertain correct model implementation. Cross-validation consisted of a comparison between ECHO-T2DM predictions and those of the seminal National Institutes of Health model. In external validation, study characteristics were entered into ECHO-T2DM to replicate the clinical results of 12 studies (including 17 patient populations), and model predictions were compared to observed values using established statistical techniques as well as measures of average prediction error, separately for the four sets of macrovascular risk equations supported in ECHO-T2DM. Sub-group analyses were conducted for dependent vs. independent outcomes and for microvascular vs. macrovascular vs. mortality endpoints. All stress tests were passed. ECHO-T2DM replicated the National Institutes of Health cost-effectiveness application with numerically similar results. In external validation of ECHO-T2DM, model predictions agreed well with observed clinical outcomes. For all sets of macrovascular risk equations, the results were close to the intercept and slope coefficients corresponding to a perfect match, resulting in high R 2 and failure to reject concordance using an F test. The results were similar for sub-groups of dependent and independent validation, with some degree of under-prediction of macrovascular events. ECHO-T2DM continues to match health outcomes in clinical trials in T2DM, with prediction accuracy similar to other leading models of T2DM.

Cardiovascular outcome clinical trials in type 2 diabetes mellitus: what are the epidemiological and methodological evidence and the first evaluations to date?

Clinical trials of glucose-lowering strategies in patients with type 2 diabetes mellitus (T2DM) have shown a favorable effect of intensive glycemic control on microvascular complications but failed to show a clear benefit on cardiovascular events. In 2008, the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) have required stringent criteria to approve new glucose-lowering drugs, demanding proof of cardiovascular safety. As a result of these regulatory requirements, a number of cardiovascular outcome trials in T2DM have been conducted examining the cardiovascular safety of novel glucose-lowering drugs. Dipeptidyl peptidase 4 (DPP4) inhibitors, analogs of glucagon-like peptide 1 (GLP-1), and inhibitors of the renal sodium-glucose linked transporter-2 (SGLT2) are new classes of glucose-lowering drugs for subjects with T2DM. The results of the cardiovascular outcome trials comparing the DPP4 inhibitors saxagliptin, alogliptin, and sitagliptin or the GLP-1 analog lixisenatide to placebo have demonstrated that these drugs are safe. The results of a cardiovascular outcome trial comparing the SGLT2 inhibitor empagliflozin to placebo have been published. Notably, empagliflozin treatment has been associated with a significant reduction in the primary composite cardiovascular outcome. Although the question regarding the positive effect of glycemic control on cardiovascular risk is still unanswered, current evidence suggests that a multifactorial approach aimed at treating not only hyperglycemia but also classical cardiovascular risk factors is necessary in order to reduce the risk of cardiovascular events in patients with T2DM.

Multivariate analysis of the population representativeness of related clinical studies

ObjectiveTo develop a multivariate method for quantifying the population representativeness across related clinical studies and a computational method for identifying and characterizing underrepresented subgroups in clinical studies. MethodsWe extended a published metric named Generalizability Index for Study Traits (GIST) to include multiple study traits for quantifying the population representativeness of a set of related studies by assuming the independence and equal importance among all study traits. On this basis, we compared the effectiveness of GIST and multivariate GIST (mGIST) qualitatively. We further developed an algorithm called “Multivariate Underrepresented Subgroup Identification” (MAGIC) for constructing optimal combinations of distinct value intervals of multiple traits to define underrepresented subgroups in a set of related studies. Using Type 2 diabetes mellitus (T2DM) as an example, we identified and extracted frequently used quantitative eligibility criteria variables in a set of clinical studies. We profiled the T2DM target population using the National Health and Nutrition Examination Survey (NHANES) data. ResultsAccording to the mGIST scores for four example variables, i.e., age, HbA1c, BMI, and gender, the included observational T2DM studies had superior population representativeness than the interventional T2DM studies. For the interventional T2DM studies, Phase I trials had better population representativeness than Phase III trials. People at least 65years old with HbA1c value between 5.7% and 7.2% were particularly underrepresented in the included T2DM trials. These results confirmed well-known knowledge and demonstrated the effectiveness of our methods in population representativeness assessment. ConclusionsmGIST is effective at quantifying population representativeness of related clinical studies using multiple numeric study traits. MAGIC identifies underrepresented subgroups in clinical studies. Both data-driven methods can be used to improve the transparency of design bias in participation selection at the research community level.

DPP4 in cardiometabolic disease: recent insights from the laboratory and clinical trials of DPP4 inhibition.

The discovery of incretin-based medications represents a major therapeutic advance in the pharmacological management of type 2 diabetes mellitus (T2DM), as these agents avoid hypoglycemia, weight gain, and simplify the management of T2DM. Dipeptidyl peptidase-4 (CD26, DPP4) inhibitors are the most widely used incretin-based therapy for the treatment of T2DM globally. DPP4 inhibitors are modestly effective in reducing HbA1c (glycated hemoglobin) (≈0.5%) and while these agents were synthesized with the understanding of the role that DPP4 plays in prolonging the half-life of incretins such as glucagon-like peptide-1 and gastric inhibitory peptide, it is now recognized that incretins are only one of many targets of DPP4. The widespread expression of DPP4 on blood vessels, myocardium, and myeloid cells and the nonenzymatic function of CD26 as a signaling and binding protein, across a wide range of species, suggest a teleological role in cardiovascular regulation and inflammation. Indeed, DPP4 is upregulated in proinflammatory states including obesity, T2DM, and atherosclerosis. Consistent with this maladaptive role, the effects of DPP4 inhibition seem to exert a protective role in cardiovascular disease at least in preclinical animal models. Although 2 large clinical trials suggest a neutral effect on cardiovascular end points, current limitations of performing trials in T2DM over a limited time horizon on top of maximal medical therapy must be acknowledged before rendering judgment on the cardiovascular efficacy of these agents. This review will critically review the science of DPP4 and the effects of DPP4 inhibitors on the cardiovascular system.

Concomitant Reduction in Low-Density Lipoprotein Cholesterol and Glycated Hemoglobin With Colesevelam Hydrochloride in Patients With Type 2 Diabetes: A Pooled Analysis

Colesevelam hydrochloride (COL), a bile acid sequestrant indicated as an adjunct to diet and exercise for reducing low-density lipoprotein cholesterol (LDL-C) in patients with primary hypercholesterolemia, was shown in a pilot study to reduce both glycated hemoglobin (HbA1c) and LDL-C in patients with type 2 diabetes mellitus (T2DM). Three double-blind, placebo-controlled trials in T2DM have now independently confirmed the HbA1c and LDL-C reductions with COL. In each of the primary studies, a significant mean treatment difference in HbA1c (-0.54%, -0.50%, and -0.54%) and LDL-C (-15.9%, -12.8%, and -16.7%) resulted from the addition of 3.75 grams/day of COL to existing metformin, insulin, or sulfonylurea-based therapy, respectively, in patients with T2DM inadequately controlled on their current antidiabetic regimen. Here we report the results of a pooled analysis of data for the 1018 patients included in the three primary studies. By study end, HbA1c, fasting plasma glucose (FPG), LDL-C, total cholesterol (TC), non-high-density lipoprotein cholesterol (HDL-C), apolipoprotein B (ApoB), and high-sensitivity C-reactive protein (hsCRP) were significantly reduced with COL versus placebo. Triglyceride (TG) and ApoA-I were significantly increased in the COL group relative to placebo. HDL-C did not change in either group, and the between-group treatment difference was small and not significant. Results of this pooled analysis are consistent with results reported previously in each of the primary COL studies and indicate that the HbA1c and LDL-C-lowering effects of COL are consistent, occurring regardless of whether COL is added to metformin, insulin, or sulfonylurea-based therapy. In conclusion, COL represents a novel therapeutic option by significantly lowering both LDL-C and HbA1c in patients with T2DM, two important treatment goals to forestall vascular complications.

The DPP‐4 inhibitor vildagliptin: robust glycaemic control in type 2 diabetes and beyond

Vildagliptin is a potent selective inhibitor of dipeptidyl peptidase-4 (DPP-4) that improves glycaemic control by increasing islet alpha-cell and beta-cell responsiveness to glucose. In patients with type 2 diabetes mellitus (T2DM), vildagliptin improves beta-cell function, measured as insulin secretory rate relative to glucose level, and reduces glucagon secretion and endogenous glucose production in the postprandial period, resulting in reduced glucose levels. In clinical trials in T2DM, vildagliptin 100 mg/day monotherapy is effective in reducing haemoglobin A1c (HbA1c) across the spectrum of hyperglycaemia and has maintained efficacy over long-term treatment with neutral effects on body weight and lipids. Vildagliptin is associated with a low risk of hypoglycaemia, and has an adverse event profile comparable to placebo, including a reduced rate of gastrointestinal adverse effects compared with metformin and a reduced rate of oedema compared with rosiglitazone. As add-on combination therapy, vildagliptin produces significant further reductions in HbA1c in patients receiving metformin, pioglitazone, glimepiride and insulin, and has been found to reduce frequency of hypoglycaemia as an add-on to insulin. Preliminary findings indicate that the improved islet cell function underlying the efficacy of vildagliptin in T2DM is also observed in patients with impaired glucose tolerance, with vildagliptin treatment resulting in reduced glycaemic excursions. The overall profile of vildagliptin and the preliminary evidence of beneficial effects in the prediabetic state suggest that DPP-4 inhibition could be an effective strategy to prevent or delay progression from the prediabetic state to overt T2DM.