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Aim: To describe the use of composite endpoints (CEs) in cardiovascular outcome trials (CVOTs) of type 2 diabetes and to evaluate the significance of the individual outcomes included within these CEs from the perspectives of both patients and clinicians. Secondary objectives were to estimate the gradient of treatment effects and events across outcomes. Materials and Methods: Eligible studies were randomized controlled trials assessing CV outcomes for patients with diabetes from 2008 and onwards. Trials were identified by searching the reports from the CVOT Summit of the Diabetes & CV Disease EASD (European Association for the Study of Diabetes) Study Group. The individual outcomes comprising the CE were compared for differences in importance for patients and clinicians, proportion of events, and effect size. Results: We included 22 trials randomizing a mean of 8098 patients to an active intervention or a comparator group for an average of 33 months (standard deviation 16). All primary outcomes were CEs, and from a patient perspective there was no gradient of importance across outcomes in 22 of 22 (100%) CEs, while the gradient was small in 22 of 22 (100%) from a clinician perspective. The gradient of effect was moderate to large in 9 of 18 (50%) reporting studies, while assessment of events was available in 15 of 22 studies (68%), finding that three of 15 (20%) had a gradient of effect of more than 5% points between included outcomes. In 10 of 22 (45%) trial reports, the results were not clearly presented as based on a CE. Conclusions: To avoid misinterpretation, clinicians and regulatory authorities should be careful when interpreting the results of trials, of which the main outcomes are CEs. [ABSTRACT FROM AUTHOR]

We have explored several statistical approaches to impute missing time-to-event data that arise from outcome trials with relatively long follow-up periods. Aligning with the primary estimand, such analyses evaluate the robustness of results by imposing an assumption different from censoring at random (CAR). Although there have been debates over which assumption and which method is more appropriate to be applied to the imputation, we propose to use the collection of retrieved dropouts as the basis of missing data imputation. As retrieved dropouts share a similar disposition, such as treatment discontinuation, with subjects who have missing data, they can reasonably be assumed to characterize the distribution of time-to-event among subjects with missing data. In terms of computational intensity and robustness to violation of underlying distributional assumption, we have compared parametric approaches via MCMC or MLE multivariate sampling procedures to a non-parametric bootstrap approach with respect to baseline hazard function. Each of these approaches follows a process of multiple imputation ("proper imputations"), analysis of complete datasets, and final combination. The type-I error, and power rates are examined under a wide range of scenarios to inform the performance characteristics. A subset of a real unblinded phase III CVOT is used to demonstrate the application of the proposed approaches, compared to the Cox proportional hazards model and jump-to-reference multiple imputation. [ABSTRACT FROM AUTHOR]

Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been linked to beneficial effects on cardiovascular risk factors, blood pressure, body weight, and lipid profile, according to a substantial body of literature. Significant cardiac and renal benefits with the use of SGLT2 inhibitors have been shown in patients with type 2 diabetes, as well as in those with heart failure and/or chronic kidney disease (CKD), regardless of diabetes status, in subsequent large cardiovascular outcome trials. Thus, SGLT2 inhibitors have become a mainstay of therapy for type 2 diabetes in patients with established cardiovascular disease and CKD due to their benefits for the heart and kidneys. Based on data from randomized controlled trials and meta-analyses, this article attempts to present a thorough review of the mechanism of action, as well as the benefits of SGLT2 inhibitors for cardiac and renal protection. On the basis of a growing body of literature on diabetes and other conditions, clinical practice guidelines have been updated to suggest the use of SGLT2 inhibitors in specific patient populations. These modifications will also be concisely described, based on evidence-based medicine principles.

Atherosclerotic cardiovascular disease (ASCVD) and heart failure (HF) are two major complications of type 2 diabetes (T2DM). Cardiovascular protection is a key objective, yet not fully reached in clinical practice. Both glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) have proven their efficacy in reducing major cardiovascular events in high-risk patients with T2DM and SGLT2is in reducing hospitalization for HF in placebo-controlled randomized trials. However, real-life studies worldwide revealed that only a minority of patients with T2DM receive either a GLP-1RA or an SGLT2i and surprisingly even less patients with established ASCVD or HF are treated with these cardioprotective antihyperglycemic agents. Bridging the gap between evidence-based cardiovascular protection with GLP-1RAs and SGLT2is and their underuse in daily clinical practice in patients with T2DM at high risk is crucial from a public health viewpoint. However, the task appears hazardous and the goal not attained considering the current failure. Education of specialists/primary care physicians and patients is critical. Multifaceted and coordinated interventions involving all actors (physicians, patients and broadly health-care system) must be implemented to stimulate the adoption of these cardioprotective antihyperglycemic medications as part of routine cardiovascular care among patients with T2DM. Type 2 diabetes can lead to major cardiovascular complications including cardiovascular disease linked to narrowing of the arteries (atherosclerosis), and heart failure. These complications are associated with lower quality of life and life expectancy. Thus, cardiovascular protection in people with type 2 diabetes is an important objective. However, clinical practice often fails in fully achieving this goal. Two types of medications that lower blood sugar (so-called antidiabetic agents) have shown efficacy in reducing major cardiovascular events (such as strokes and heart attacks) in high-risk patients with type 2 diabetes. One of them has also shown effectiveness in decreasing hospitalizations due to heart failure. However, in clinical practice, most patients with type 2 diabetes do not receive these medications, even people with known cardiovascular disease or heart failure, despite the proven effectiveness of these drugs. Many studies worldwide have highlighted socioeconomic inequities regarding the use of these medications, which can be expensive. From a public health perspective, it is imperative to bridge the gap between the under-use of cardioprotective antidiabetic agents in routine daily practice among high-risk patients with type 2 diabetes and the clear-cut recommendations of international guidelines. Given the current limitations, this task appears challenging. Education of physicians (both primary care practitioners and specialists, including cardiologists) and patients is most important in addressing this issue. Finally, in every country, the global health-care system should facilitate the use of these agents among patients with type 2 diabetes at high risk of atherosclerotic cardiovascular disease and heart failure. [ABSTRACT FROM AUTHOR]

Recently, retrieved-dropout-based multiple imputation has been used in some therapeutic areas to address the treatment policy estimand, mostly for continuous endpoints. In this approach, data from subjects who discontinued study treatment but remained in study were used to construct a model for multiple imputation for the missing data of subjects in the same treatment arm who discontinued study. We extend this approach to time-to-event endpoints and provide a practical guide for its implementation. We use a cardiovascular outcome trial dataset to illustrate the method and compare the results with those from Cox proportional hazard and reference-based multiple imputation methods. [ABSTRACT FROM AUTHOR]

Abstract Background Cardiovascular outcome trials (CVOTs) are conducted on a background of standard of care including metformin. These analyses sought to determine whether the cardiovascular (CV) effects of semaglutide and other glucagon-like peptide-1 receptor agonists (GLP-1RAs) vary according to baseline metformin use. Methods A post hoc analysis was conducted using pooled SUSTAIN 6 and PIONEER 6 CVOT data in subjects with and without metformin use at baseline. Additionally, a trial-level meta-analysis was conducted using data from seven CVOTs with GLP-1RAs–SUSTAIN 6, PIONEER 6, HARMONY OUTCOMES, LEADER, REWIND, EXSCEL and AMPLITUDE-O–including adults with type 2 diabetes at high CV risk, and a primary endpoint of time to first major adverse CV event (MACE). Results In the post hoc analysis, the no-metformin subgroup was older, with a higher body mass index, lower estimated glomerular filtration rate and higher CV risk at baseline vs the metformin subgroup. Hazard ratios (95% confidence intervals) for the reduction in risk of MACE with semaglutide vs placebo in the metformin and no-metformin subgroups were 0.70 (0.55;0.89) and 0.86 (0.60;1.22), respectively. No significant interaction between the treatment effect on MACE and metformin subgroup was observed. Findings for other CV endpoints were similar. In the meta-analysis, treatment effect (GLP-1RA vs placebo) on CV outcomes was no different with vs without baseline metformin (overall ratio between the hazard ratios for metformin vs no-metformin 1.09 [0.96;1.22]). Conclusion These findings indicate that the CV outcomes for semaglutide were similar regardless of baseline metformin use, which may also apply to all GLP-1RAs. Trial registration SUSTAIN 6 (NCT01720446), PIONEER 6 (NCT02692716).

Aims: Treatment effects from the large cardiovascular outcome trials (CVOTs) of new antidiabetic drugs are almost exclusively communicated as hazard ratios, although reporting guidelines recommend to report treatment effects also on an absolute scale, e.g. as numbers needed to treat (NNT). We aimed to analyse NNTs in CVOTs comparing dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, or sodium–glucose cotransporter-2 (SGLT2) inhibitors to placebo. Methods: We digitalized individual time-to-event information for the primary outcome and all-cause mortality from 19 CVOTs that compared DPP-4 inhibitors, GLP-1 receptor agonists, or SGLT2 inhibitors to placebo. We estimated Weibull models for each trial and outcome and derived monthly NNTs. NNTs were summarized across all trials and within drug classes by random effects meta-analysis methods. Results: Treatment effects in the CVOTs appear smaller if they are reported as NNTs: Overall, 100 (95%-CI: 60, 303) patients have to be treated for 29 months (the median follow-up time across all trials) to avoid a single event of the primary outcome, and 128 (95%-CI: 85, 265) patients have to be treated for 39 months to avoid a single death. NNT time courses are very similar for GLP-1 receptor agonists and SGLT2 inhibitors, whereas treatment effects with DPP-4 inhibitors are smaller. Conclusions: We found that the respective treatment effects look less impressive when communicated on an absolute scale, as numbers needed to treat. For a valid overall picture of the benefit of new antidiabetic drugs, trial authors should also report treatment effects on an absolute scale. [ABSTRACT FROM AUTHOR]

Abstract Background Recent treatment guidelines support the use of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in patients with type 2 diabetes and cardiovascular disease based on the results of cardiovascular outcome trials (CVOTs). Applicability of these trials to everyday patients with type 2 diabetes and cardiovascular disease is however unknown. The aim of this study is to assess the external applicability of SGLT2i CVOTs in daily clinical practice type 2 diabetes patients with established cardiovascular disease. Methods Trial in- and exclusion criteria from EMPA-REG OUTCOME, CANVAS, DECLARE-TIMI 58 and VERTIS-CV were applied to 1389 type 2 diabetes patients with cardiovascular disease in the Utrecht Cardiovascular Cohort-Secondary Manifestations of ARTerial disease (UCC-SMART). To evaluate the difference in cardiovascular risk (MACE) and all-cause mortality between trial eligible and ineligible patients, age and sex-adjusted Cox-regression analyses were performed. Results After applying trial in- and exclusion criteria, 48% of UCC-SMART patients with type 2 diabetes and cardiovascular disease would have been eligible for DECLARE-TIMI 58, 35% for CANVAS, 29% for EMPA-REG OUTCOME and 21% for VERTIS-CV. Without the eligibility criteria of HbA1c, eligibility was 58–88%. For all trials the observed risk for cardiovascular events and all-cause mortality was similar in eligible and ineligible patients after adjustment for age and gender. Conclusion A large proportion of patients with type 2 diabetes and cardiovascular disease in daily clinical practice would have been eligible for participation in the SGLT2i CVOTs. Trial eligible and ineligible patients have the same risk for MACE and all-cause mortality.

Safety evaluation is a continual and iterative process throughout the drug development life cycle and requires long time horizons and large amounts of data to fully understand the safety profile of a medical product. Although randomized clinical trials (RCT) provide high-quality data for an initial assessment of safety signals, the safety signals may not all have been known at the time of approval because safety data collected from RCT only involve a relatively small number of subjects during a relatively short follow-up period. The increased accumulation of post-marketing real-world data (RWD) presents an opportunity to utilize them for safety decision-making; these include identifying new safety signals, further characterization of safety concerns that are raised in pre-marketing RCT, and further generalization of RCT findings to the broader patient populations not previously studied in RCT. In this paper, we use cardiovascular safety outcome trial for antidiabetic therapies as an illustrative example and discuss how integrative analysis of RCT and observational study data can answer regulatory concerns about cardiovascular risk in a post-marketing setting. A novel statistical analysis strategy is proposed to combine both sources of safety data in a data fusion approach. The proposed approach includes three stages: (1) feasibility analysis that uses an RCT to validate an observational study, applying estimand framework and emulating RCT with RWD; (2) integrative analysis that combines evidence from the RCT and observational study data cooperatively; and (3) sensitivity analysis that examines the consistency of the previous analyses. Two potential utilities of the proposed integrative analysis for the cardiovascular safety outcome trial are discussed. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular outcome trials (CVOTs) are conducted on a background of standard of care including metformin. These analyses sought to determine whether the cardiovascular (CV) effects of semaglutide and other glucagon-like peptide-1 receptor agonists (GLP-1RAs) vary according to baseline metformin use. Methods: A post hoc analysis was conducted using pooled SUSTAIN 6 and PIONEER 6 CVOT data in subjects with and without metformin use at baseline. Additionally, a trial-level meta-analysis was conducted using data from seven CVOTs with GLP-1RAs–SUSTAIN 6, PIONEER 6, HARMONY OUTCOMES, LEADER, REWIND, EXSCEL and AMPLITUDE-O–including adults with type 2 diabetes at high CV risk, and a primary endpoint of time to first major adverse CV event (MACE). Results: In the post hoc analysis, the no-metformin subgroup was older, with a higher body mass index, lower estimated glomerular filtration rate and higher CV risk at baseline vs the metformin subgroup. Hazard ratios (95% confidence intervals) for the reduction in risk of MACE with semaglutide vs placebo in the metformin and no-metformin subgroups were 0.70 (0.55;0.89) and 0.86 (0.60;1.22), respectively. No significant interaction between the treatment effect on MACE and metformin subgroup was observed. Findings for other CV endpoints were similar. In the meta-analysis, treatment effect (GLP-1RA vs placebo) on CV outcomes was no different with vs without baseline metformin (overall ratio between the hazard ratios for metformin vs no-metformin 1.09 [0.96;1.22]). Conclusion: These findings indicate that the CV outcomes for semaglutide were similar regardless of baseline metformin use, which may also apply to all GLP-1RAs. Trial registration SUSTAIN 6 (NCT01720446), PIONEER 6 (NCT02692716). [ABSTRACT FROM AUTHOR]

Cardiovascular outcome trials (CVOTs) have to be done by sponsors who wish to launch new antidiabetic drugs in the US, since the December 2008 US Food and Drug Administration ruling, which was subsequently accepted by the European Medicines (Evaluation) Agency (EMA) in 2012. However, the medical community asks the question, “So What?” as they are not convinced of the clinical relevance of CVOTs. The patients selected in CVOTs are necessarily high risk, so that they develop major adverse cardiovascular events quickly, but then, the results are extrapolatable to only a certain percentage of patients seen in the clinical practice. Doctors believe that these trials only serve a regulatory need. At the same time, these trials do provide a lot of good data, but it needs to be interpreted well, and extrapolated appropriately to patients in practice as there are differences between what happens in a randomized control trial and in the real world. Hence, the need for this article which serves to dissect the CVOTs of sodium-glucose co-transporter-2 inhibitors, so that doctors are able to better read this evidence. However, the question of which gliflozin is the best cannot be answered by these trials as these are not head to head trials. All the more reason why one needs to look at the data holistically and be empowered to make the right decision for individual patients, hoping to match the best patient for the best drug, rather than determine which drug is better.

Cardiovascular outcome trials revealed cardiovascular benefits for type 2 diabetes mellitus patients when treated with long‐acting glucagon‐like peptide‐1 (GLP‐1) receptor agonists. In the last decade, major advances were made characterising the physiological effects of GLP‐1 and its action on numerous targets including brain, liver, kidney, heart and blood vessels. However, the effects of GLP‐1 and receptor agonists, and the GLP‐1 receptor on the cardiovascular system have not been fully elucidated. We compare results from cardiovascular outcome trials of GLP‐1 receptor agonists and review pleiotropic clinical and preclinical data concerning cardiovascular protection beyond glycaemic control. We address current knowledge on GLP‐1 and receptor agonist actions on the heart, vasculature, inflammatory cells and platelets, and discuss evidence for GLP‐1 receptor‐dependent versus independent effects secondary of GLP‐1 metabolites. We conclude that the favourable cardiovascular profile of GLP‐1 receptor agonists might expand their therapeutic use for treating cardiovascular disease even in non‐diabetic populations. LINKED ARTICLES: This article is part of a themed issue on GLP1 receptor ligands (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.4/issuetoc [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Several cardiovascular outcome trials on sodium–glucose cotransporter 2 inhibitors (SGLT2i) have been released recently, including trials enrolling patients with congestive heart failure (CHF) and chronic kidney disease (CKD). Comparisons of the efficacy and safety of SGLT2i, glucagon-like peptide-1 receptor agonists (GLP-1RA) and dipeptidyl peptidase-4 inhibitors (DPP-4i) thus require an update. Assessments in patient subgroups, i.e., as stratified by age or the presence of CHF, CKD or atherosclerotic cardiovascular disease (ASCVD), are also currently lacking. Methods: We searched the PubMed, Embase and Cochrane databases for relevant studies published up until 5 December 2020. RCTs comparing SGLT2i, GLP-1RA and DPP-4i with placebo (or other controls) or with each other with cardiovascular (CV) or renal outcomes were eligible for inclusion. The primary efficacy endpoint was 3-point major adverse cardiovascular events (3P-MACE), which are defined as CV death, non-fatal myocardial infarction and non-fatal ischaemic stroke. All-cause mortality, hospitalisation for heart failure (HHF) and composite renal outcomes were also analysed. Pre-specified subgroup analyses of 3P-MACE were also performed. Results: A total of 21 trials with 170,930 participants were included in this network meta-analysis. Both GLP-1RA and SGLT2i were associated with lower risks of 3P-MACE than placebo (RR 0.89, 95% CI 0.84, 0.94 and RR 0.88, 95% CI 0.83, 0.94, respectively). GLP-1RA and SGLT2i were also associated with lower risks of 3P-MACE than DPP-4i (RR 0.89, 95% CI 0.82, 0.98 and RR 0.89, 95% CI 0.81, 0.97, respectively). A comparison between SGLT2i and GLP-1RA demonstrated no difference in their risks of 3P-MACE (RR 0.99, 95% CI 0.91, 1.08). Only GLP-1RA was associated with a lower risk of stroke compared with placebo (RR 0.85, 95% CI 0.76, 0.94). SGLT2i is superior to GLP-1RA in reducing HHF (RR 0.76, 95% CI 0.68, 0.84) and renal outcomes (RR 0.78, 95% CI 0.65, 0.93). Subgroup analyses indicated that the benefits of SGLT2i and GLP-1RA were more pronounced in elderly patients, white and Asian patients, those with established ASCVD and those with longer durations of diabetes mellitus and worse glycaemic control. Conclusions/interpretation: SGLT2i and GLP-1RA are superior to DPP-4i in terms of CV and renal outcomes. GLP-1RA is the only drug class that reduces the risk of stroke. SGLT2i is superior in reducing HHF and renal outcomes. Therefore, the choice between SGLT2i and GLP-1RA should be individualised according to patient profiles. PROSPERO registration number: CRD42020206600. [ABSTRACT FROM AUTHOR]

Abstract The recent results of Cardiovascular Outcomes Trials (CVOTs) in type 2 diabetes have clearly established the cardiovascular (CV) safety or even the benefit of two therapeutic classes, Glucagon-Like Peptide-1 receptor agonists (GLP-1 RA) and Sodium-Glucose Co-Transporter-2 inhibitors (SGLT-2i). Publication of the latest CVOTs for these therapeutic classes also led to an update of ESC guidelines and ADA/EASD consensus report in 2019, which considers using GLP-1 RA or SGLT-2i with proven cardiovascular benefit early in the management of type 2 diabetic patient with established cardiovascular disease (CVD) or at high risk of atherosclerotic CVD. The main beneficial results of these time-to event studies are supported by conventional statistical measures attesting the effectiveness of GLP-1 RA or SGLT2i on cardiovascular events (absolute risk, absolute risk difference, relative risk, relative risk reduction, odds ratio, hazard ratio). In addition, another measure whose clinical meaning appears to be easier, the Number Needed to Treat (NNT), is often mentioned while discussing the results of CVOTs, in order to estimating the clinical utility of each drug or sometimes trying to establish a power ranking. While the value of the measure is admittedly of interest, the subtleties of its computation in time-to-event studies are little known. We provide in this article a clear and practical explanation on NNT computation methods that should be used in order to estimate its value, according to the type of study design and variables available to describe the event of interest, in any randomized controlled trial. More specifically, a focus is made on time-to-event studies of which CVOTs are part, first to describe in detail an appropriate and adjusted method of NNT computation and second to help properly interpreting NNTs with the example of CVOTs conducted with GLP-1 RA and SGLT-2i. We particularly discuss the risk of misunderstanding of NNT values in CVOTs when some specific parameters inherent in each study are not taken into account, and the following risk of erroneous comparison between NNTs across studies. The present paper highlights the importance of understanding rightfully NNTs from CVOTs and their clinical impact to get the full picture of a drug’s effectiveness.

Introduction: Patients with type 2 diabetes (T2DM) are at high risk of atherosclerotic cardiovascular disease (ASCVD) and cardiovascular death. Cardiovascular protection is a key objective in T2DM., Areas Covered: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have proven their efficacy in reducing major cardiovascular events in high-risk patients with T2DM in placebo-controlled trials, a finding confirmed in observational studies compared with other glucose-lowering agents. Overall, GLP-1RAs have a good safety profile associated with a favorable benefit/risk ratio for the management of T2DM, even if their cost-effectiveness might be questionable. International guidelines recommend GLP-1RAs as preferred glucose-lowering agents in patients with ASCVD and as a valuable alternative in overweight/obese patients with T2DM. However, real-life studies worldwide revealed that only a minority of patients receive a GLP-1RA, despite a positive trend for increased prescriptions in recent years. Surprisingly, however, fewer patients with established ASCVD are treated with these cardioprotective antihyperglycemic agents versus patients without ASCVD., Expert Opinion: The reasons for GLP-1RA underuse in clinical practice are multiple. Multifaceted and coordinated interventions targeting all actors of the health-care system must be implemented to stimulate the adoption of GLP-1RAs as part of routine cardiovascular care among patients with T2DM, especially in those with ASCVD.

Background: Recent treatment guidelines support the use of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in patients with type 2 diabetes and cardiovascular disease based on the results of cardiovascular outcome trials (CVOTs). Applicability of these trials to everyday patients with type 2 diabetes and cardiovascular disease is however unknown. The aim of this study is to assess the external applicability of SGLT2i CVOTs in daily clinical practice type 2 diabetes patients with established cardiovascular disease. Methods: Trial in- and exclusion criteria from EMPA-REG OUTCOME, CANVAS, DECLARE-TIMI 58 and VERTIS-CV were applied to 1389 type 2 diabetes patients with cardiovascular disease in the Utrecht Cardiovascular Cohort-Secondary Manifestations of ARTerial disease (UCC-SMART). To evaluate the difference in cardiovascular risk (MACE) and all-cause mortality between trial eligible and ineligible patients, age and sex-adjusted Cox-regression analyses were performed. Results: After applying trial in- and exclusion criteria, 48% of UCC-SMART patients with type 2 diabetes and cardiovascular disease would have been eligible for DECLARE-TIMI 58, 35% for CANVAS, 29% for EMPA-REG OUTCOME and 21% for VERTIS-CV. Without the eligibility criteria of HbA1c, eligibility was 58–88%. For all trials the observed risk for cardiovascular events and all-cause mortality was similar in eligible and ineligible patients after adjustment for age and gender. Conclusion: A large proportion of patients with type 2 diabetes and cardiovascular disease in daily clinical practice would have been eligible for participation in the SGLT2i CVOTs. Trial eligible and ineligible patients have the same risk for MACE and all-cause mortality. [ABSTRACT FROM AUTHOR]

Introduction: Since 2008 United State (US) food drug administration mandate, several newer anti-diabetic drugs (ADD) have undergone a mandatory cardiovascular (CV) outcome trial (CVOT) in type diabetes (T2DM) patients with high CV risk. These includes CVOT done with dipeptidyl-peptidase-4 inhibitors, sodium-glucose co-transporter-2 inhibitors and glucagon-like peptide-1 receptor agonist (GLP-1RAs). Several double-blind, randomized, placebo-controlled CVOT have been presented and published in the last decade (2008-2018). Aims and Objectives: We systematically searched the database of PubMed and ClinicalTrials.gov from January 1, 2008 to December 31, 2018 using specific key words. Subsequently, we pooled the data of different cardiovascular endpoints and made a comparative forest plot using GraphPad software Inc. Prism Version 8, US. Results and Conclusion: Saxagliptin, alogliptin, sitagliptin and linagliptin are CV neutral drugs. Saxagliptin showed a significantly higher hospitalization due to heart failure (HHF). Empagliflozin and canagliflozin have shown a significant reduction in composite of 3-point major cardiac adverse events (3P-MACE). Additionally, empagliflozin, canagliflozin and dapagliflozin significantly reduced the HHF and the composite of CV death or HHF. Moreover, empagliflozin showed significant reduction in CV- and all-cause death in patients with T2DM with established CV disease. While both exendin-backbone-based GLP-1RAs such as lixisenatide and extended-release exenatide were CV neutral; GLP-1-backbone-based GLP-1RAs such as liraglutide, semaglutide and albiglutide shown a significant reduction in the composite of 3-P MACE. Additionally, liraglutide shown a significant reduction in CV- and all-cause death. Moreover, semaglutide reduced non-fatal stroke and albiglutide reduced myocardial infarction, while extended-release exenatide reduced all-cause death; however, P value of significance for these outcomes should be considered nominal.

Cardiovascular outcome trials (CVOTs) have to be done by sponsors who wish to launch new antidiabetic drugs in the US, since the December 2008 US Food and Drug Administration ruling, which was subsequently accepted by the European Medicines (Evaluation) Agency (EMA) in 2012. However, the medical community asks the question, "So What?" as they are not convinced of the clinical relevance of CVOTs. The patients selected in CVOTs are necessarily high risk, so that they develop major adverse cardiovascular events quickly, but then, the results are extrapolatable to only a certain percentage of patients seen in the clinical practice. Doctors believe that these trials only serve a regulatory need. At the same time, these trials do provide a lot of good data, but it needs to be interpreted well, and extrapolated appropriately to patients in practice as there are differences between what happens in a randomized control trial and in the real world. Hence, the need for this article which serves to dissect the CVOTs of sodium-glucose co-transporter-2 inhibitors, so that doctors are able to better read this evidence. However, the question of which gliflozin is the best cannot be answered by these trials as these are not head to head trials. All the more reason why one needs to look at the data holistically and be empowered to make the right decision for individual patients, hoping to match the best patient for the best drug, rather than determine which drug is better. [ABSTRACT FROM AUTHOR]

Abstract In Japan, the choice of anti-diabetic medication is officially recommended according to the patient’s glycemic condition and disease phenotype, unlike most other regions where metformin is recommended as the first-line medication. There has been an increase in the number of available glucose-lowering agents, making it necessary to select these agents based on ever-improving evidence obtained from clinical trials. For the dipeptidyl peptidase-4 inhibitor class of drugs, nine drugs are currently available on the market in Japan. Although previous cardiovascular outcome trials (CVOTs) demonstrated non-inferiority for both major adverse cardiovascular events (MACEs) and safety for some drugs of the class, the design and results of the CARMELINA trial seemed to be slightly different from earlier trials in that it showed the drugs were safe and partially effective even in patients with renal impairment. Thus, recent CVOTs on newer glucose-lowering agents have mainly focused on the major impacts of individual classes and drugs on clinical outcomes behind their glucose-lowering action. The diverse features of the classes and individual drugs may have also highlighted not only the class-effects, but also the drug-effects of glucose-lowering agents. This will lead to clinical-based evidence and assist with optimum selection of the class and/or drug for tailored medication in patients with type 2 diabetes.

Data from three completed cardiovascular outcome trials (CVOTs), EMPA‐REG OUTCOME, CANVAS Program and DECLARE‐TIMI 58, add to the evidence supporting the potential renoprotective effects of sodium‐glucose linked transporter‐2 (SGLT2) inhibitors in patients with type 2 diabetes. Despite recommendations in recent guidelines, it is difficult to support a view that definitive evidence for renoprotection exists from these SGLT2 inhibitor CVOT results. To date, the only dedicated trial to report definitive data on the renal impact of SGLT2 inhibition is CREDENCE. Notably, the total number of patient‐relevant renal endpoint events (dialysis, transplant or renal death) observed in CREDENCE was significantly higher than the total for all three CVOTs collectively (183 events/4401 patients vs. 69 events/34 322 patients, respectively), which shows the increased statistical power of CREDENCE for these renal endpoints. Treatment with canagliflozin was associated with a 30% relative risk reduction (RRR) in the primary composite endpoint of end‐stage kidney disease, doubling of serum creatinine, or death from renal or cardiovascular causes and a 34% RRR for the renal‐specific elements of this primary endpoint (P <0.001). Canagliflozin has therefore become the first US‐approved SGLT2 inhibitor to include an indication for RRR, in addition to type 2 diabetes glycaemic control and cardiovascular risk reduction. While confirmatory of the exploratory data from CVOTs, CREDENCE provides the first robust data on the effects of canagliflozin on patient‐relevant renal endpoints. Extrapolation to a conclusion of a SGLT2 inhibitor class effect cannot be made until additional renal trials with other SGLT2 inhibitors are reported. [ABSTRACT FROM AUTHOR]

In recent years, successive reports have been made on large-scale cardiovascular outcome trials using novel hypoglycemic drugs. Their results have shown that sodium–glucose cotransporter 2 (SGLT2) inhibitors are hypoglycemic drugs that could potentially greatly improve the heart failure-related outcomes in type 2 diabetes patients with a high cardiovascular risk. Further analyses have subsequently been performed from various perspectives, and SGLT2 inhibitors with their class effect have been indicated to be potentially useful for heart failure in type 2 diabetes patients with extensive clinical background. As a result, a clear concept has globally emerged with SGLT2 inhibitors as drugs of choice in clinical practice to prevent heart failure in type 2 diabetes patients. Further studies are needed to examine the next research topics on heart failure prevention using SGLT2 inhibitors, including their detailed pharmacological mechanism of action and their effectiveness and safety against heart failure in patients regardless of diabetes status. This paper outlines (1) the current evidence of heart failure prevention by SGLT2 inhibitors based on the results of recent large-scale cardiovascular outcome trials and (2) future research topics on their further applications in clinical practice. [ABSTRACT FROM AUTHOR]

The recent results of Cardiovascular Outcomes Trials (CVOTs) in type 2 diabetes have clearly established the cardiovascular (CV) safety or even the benefit of two therapeutic classes, Glucagon-Like Peptide-1 receptor agonists (GLP-1 RA) and Sodium-Glucose Co-Transporter-2 inhibitors (SGLT-2i). Publication of the latest CVOTs for these therapeutic classes also led to an update of ESC guidelines and ADA/EASD consensus report in 2019, which considers using GLP-1 RA or SGLT-2i with proven cardiovascular benefit early in the management of type 2 diabetic patient with established cardiovascular disease (CVD) or at high risk of atherosclerotic CVD. The main beneficial results of these time-to event studies are supported by conventional statistical measures attesting the effectiveness of GLP-1 RA or SGLT2i on cardiovascular events (absolute risk, absolute risk difference, relative risk, relative risk reduction, odds ratio, hazard ratio). In addition, another measure whose clinical meaning appears to be easier, the Number Needed to Treat (NNT), is often mentioned while discussing the results of CVOTs, in order to estimating the clinical utility of each drug or sometimes trying to establish a power ranking. While the value of the measure is admittedly of interest, the subtleties of its computation in time-to-event studies are little known. We provide in this article a clear and practical explanation on NNT computation methods that should be used in order to estimate its value, according to the type of study design and variables available to describe the event of interest, in any randomized controlled trial. More specifically, a focus is made on time-to-event studies of which CVOTs are part, first to describe in detail an appropriate and adjusted method of NNT computation and second to help properly interpreting NNTs with the example of CVOTs conducted with GLP-1 RA and SGLT-2i. We particularly discuss the risk of misunderstanding of NNT values in CVOTs when some specific parameters inherent in each study are not taken into account, and the following risk of erroneous comparison between NNTs across studies. The present paper highlights the importance of understanding rightfully NNTs from CVOTs and their clinical impact to get the full picture of a drug's effectiveness. [ABSTRACT FROM AUTHOR]

People with diabetes mellitus are at higher risk of ischaemic stroke and worse outcomes thereafter. However, whether it is better to prescribe intensive glucose‐lowering treatment compared with conventional treatment in people with diabetes to prevent recurrent stroke is debated. It is also crucial to consider whether specific antidiabetic agents are more efficacious and safer than others for prevention of stroke. In this review, we provide an overview of the efficacy of intensive and conventional glucose‐lowering treatment in post‐stroke management. Our conclusion is that the overall evidence for a beneficial effect of intensive glycaemic control on risk of stroke is limited. We also discuss evidence from recent large clinical trials of thiazolidinediones and new antidiabetic medications, including dipeptidyl peptidase‐4 inhibitors, glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs), and sodium‐glucose co‐transporter‐2 inhibitors. On the basis of the findings of these trials, our conclusion is that pioglitazone and the GLP‐1RA class (other than short‐acting lixisenatide) are likely to lessen the occurrence of cerebrovascular disease (by mechanisms not dependent on glucose‐lowering per se), whereas there is no consistent evidence for other drug classes. [ABSTRACT FROM AUTHOR]

Recently reported cardiovascular outcome studies on empagliflozin (EMPA-REG) and liraglutide (LEADER) have spurred interest in this field of diabetology. This commentary compares and contrasts these studies with two equally important outcome trials conducted using blood pressure lowering agents. A comparison with MICROHOPE (using ramipril) and ADVANCE (using perindopril + indapamide) blood pressure arms throws up interesting facts. The degree of blood pressure lowering, dissociation between cardiovascular and cerebrovascular benefits, and discordance between renal and retinal outcomes are surprisingly similar in these trials, conducted using disparate molecules. The time taken to achieve such benefits is similar for all drugs except empagliflozin. Such discussion helps inform rational and evidence-based choice of therapy and forms the framework for future research.

Background The value of glycemic control and preexisting cardiovascular disease in determining the risk of major cardiovascular events (MACE) in type 2 diabetes mellitus is uncertain. Intensive glucose control trials suggest that the 9% lower risk of MACE associated with intensive glycemic control, as compared with conventional glycemic control, is only driven by patients with type 2 diabetes mellitus without cardiovascular disease at baseline. Methods and Results We did a meta‐analysis of cardiovascular outcome trials dividing patients with or without preexisting cardiovascular disease; we found that the lower risk of MACE is confined to patients with cardiovascular disease at baseline. Compared with placebo, the use of both glucagon‐like peptide‐1 receptor agonists and sodium‐glucose cotransporter‐2 inhibitors was associated with a significant 14% lower MACE risk in patients with preexisting cardiovascular disease and with a nonsignificant 2% higher MACE risk in those without preexisting cardiovascular disease (P for interaction=0.021). The meta‐regression analysis of all 12 trials demonstrated a significant (P=0.002) association between reductions of glycated hemoglobin in glycated hemoglobin A1C. Accordingly, the reduction of MACE expected if all cardiovascular outcome trials had achieved a 0.9% glycated hemoglobin reduction would have been 33%. Routine clinical care data complement the results of cardiovascular outcome trials but with some differences: the lower risk of MACE with sodium‐glucose cotransporter‐2 inhibitor use is evident in patients with type 2 diabetes mellitus with or without preexisting cardiovascular disease. Conclusions Sodium‐glucose cotransporter‐2 inhibitors and glucagon‐like peptide‐1 receptor agonists should be included in the therapeutic plan of patients with type 2 diabetes mellitus and overt cardiovascular disease, with due attention paid to improvement of glycemic control, which may amplify their benefit on MACE.

Achieving and maintaining recommended glycemic targets without causing adverse e ffects, including hypoglycemia, is challenging, especially in older patients with type 2 diabetes mellitus (T2DM). The introduction of dipeptidyl peptidase-4 (DPP-4) inhibitors, more than 10 years ago, has provided an alternative to conventional medications for the intensification of glucose-lowering treatment after failure of metformin monotherapy, and therefore, marked an important advance in the management of T2DM. By prolonging the activity of incretin hormones, DPP-4 inhibitors induce insulin release and decrease glucagon secretion in a glucose-dependent manner. This results in a more physiologic glycemic control as compared to that ensured by insulin secretagogues (sulfonylureas and glinides). Overall, DPP-4 inhibitors have a favorable safety profile and can be used without dose adjustments in older adults and in patients with mild renal impairment; they have a neutral effect on body weight and do not cause hypoglycemia by themselves. Safety issues, reported mainly in post-marketing surveillance programs and including cardiovascular outcomes and the risk of acute pancreatitis, are being extensively investigated. The aim of this review is to discuss the impact of DPP-4 inhibitors on the treatment of T2DM, after 10 years of experience, with an emphasis on diabetes care in Italy. We will first describe T2DM treatment in Italy and then provide an overview of the main findings from randomized controlled trials, real-world studies and post-marketing surveillance programs with DPP-4 inhibitors. [ABSTRACT FROM AUTHOR]

Aims: Enrollment criteria vary substantially among cardiovascular outcome trials (CVOTs) of sodium‐glucose cotransporter‐2 inhibitors (SGLT‐2is), which impacts the relationship between a trial population and the general type 2 diabetes (T2D) population. The aim of this study was to evaluate the representativeness of four SGLT‐2i CVOTs of a general T2D population. Methods: T2D patients from Germany, The Netherlands, Norway and Sweden were included in the study. Given the available data per country, key inclusion and exclusion criteria were defined by diagnoses, procedures and drug treatments to facilitate comparability among countries. Representativeness was determined by dividing the number of patients fulfilling the key enrolment criteria of each CVOT (CANVAS, DECLARE‐TIMI 58, EMPA‐REG OUTCOME, VERTIS‐CV) by the total T2D population. Results: In 2015, a total T2D population of 803 836 patients was identified in Germany (n = 239 485), in The Netherlands (n = 36 213), in Norway (n = 149 782) and in Sweden (n = 378 356). These populations showed a 25% to 44% cardiovascular (CV) disease baseline prevalence and high CV‐preventive drug use (>80%). The general T2D population had less prevalent CV disease and patients were slightly older than those included in the CVOTs. The DECLARE‐TIMI 58 trial had the highest representativeness, 59% compared to the general T2D population, and this representativeness was almost 2‐, 3‐ and 4‐fold higher compared to the CANVAS (34%), EMPA‐REG OUTCOME (21%) and VERTIS‐CV (17%) trials, respectively. Conclusions: In large T2D populations within Europe, consistent patterns of representativeness of CVOTs were found when applying the main enrolment criteria. The DECLARE‐TMI 58 trial had the highest representativeness, indicating that it included and examined patients who are most representative of the general T2D patients in the studied countries. [ABSTRACT FROM AUTHOR]

Introduction: Since 2008 United State (US) food drug administration mandate, several newer anti-diabetic drugs (ADD) have undergone a mandatory cardiovascular (CV) outcome trial (CVOT) in type diabetes (T2DM) patients with high CV risk. These includes CVOT done with dipeptidyl-peptidase-4 inhibitors, sodium-glucose co-transporter-2 inhibitors and glucagon-like peptide-1 receptor agonist (GLP-1RAs). Several double-blind, randomized, placebo-controlled CVOT have been presented and published in the last decade (2008-2018). Aims and Objectives: We systematically searched the database of PubMed and ClinicalTrials.gov from January 1, 2008 to December 31, 2018 using specific key words. Subsequently, we pooled the data of different cardiovascular endpoints and made a comparative forest plot using GraphPad software Inc. Prism Version 8, US. Results and Conclusion: Saxagliptin, alogliptin, sitagliptin and linagliptin are CV neutral drugs. Saxagliptin showed a significantly higher hospitalization due to heart failure (HHF). Empagliflozin and canagliflozin have shown a significant reduction in composite of 3-point major cardiac adverse events (3P-MACE). Additionally, empagliflozin, canagliflozin and dapagliflozin significantly reduced the HHF and the composite of CV death or HHF. Moreover, empagliflozin showed significant reduction in CV- and all-cause death in patients with T2DM with established CV disease. While both exendin-backbone-based GLP-1RAs such as lixisenatide and extended-release exenatide were CV neutral; GLP-1-backbone-based GLP-1RAs such as liraglutide, semaglutide and albiglutide shown a significant reduction in the composite of 3-P MACE. Additionally, liraglutide shown a significant reduction in CV- and all-cause death. Moreover, semaglutide reduced non-fatal stroke and albiglutide reduced myocardial infarction, while extended-release exenatide reduced all-cause death; however, P value of significance for these outcomes should be considered nominal. [ABSTRACT FROM AUTHOR]

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a novel class of oral hypoglycemic agents which increase urinary glucose excretion by suppressing glucose reabsorption at the proximal tubule in the kidney. SGLT2 inhibitors lower glycated hemoglobin (HbA1c) by 0.6–0.8% (6–8 mmol/mol) without increasing the risk of hypoglycemia and induce weight loss and improve various metabolic parameters including blood pressure, lipid profile and hyperuricemia. Recent cardiovascular (CV) outcome trials have shown the improvement of CV and renal outcomes by treatment with the SGLT2 inhibitors, empagliflozin, canagliflozin, and dapagliflozin. The mechanisms by which SGLT2 inhibitors improve CV outcome appear not to be glucose-lowering or anti-atherosclerotic effects, but rather hemodynamic effects through osmotic diuresis and natriuresis. Generally, SGLT2 inhibitors are well-tolerated, but their adverse effects include genitourinary tract infection and dehydration. Euglycemic diabetic ketoacidosis is a rare but severe adverse event for which patients under SGLT2 inhibitor treatment should be carefully monitored. The possibility of an increase in risk of lower-extremity amputation and bone fracture has also been reported with canagliflozin. Clinical trials and real-world data have suggested that SGLT2 inhibitors improve CV and renal outcomes and mortality in patients with type 2 diabetes (T2DM), especially in those with prior CV events, heart failure, or chronic kidney disease. Results of recent trials including individuals without diabetes may change the positioning of this drug as ″a drug for cardiorenal protection″. This review summarizes the potential of SGLT2 inhibitors and discusses their role in the treatment of T2DM.

Introduction: The aim of this study was to evaluate the short-term cost-utility of insulin degludec (degludec) versus insulin glargine 100 units/mL (glargine U100) for the treatment of type 2 diabetes in the basal-bolus subgroup of the head-to-head cardiovascular (CV) outcome trial, DEVOTE.Methods: A cost-utility analysis was conducted over a 2-year time horizon using a decision analytic model to compare costs in patients receiving once daily degludec or glargine U100, both as part of a basal-bolus regimen, in addition to standard care. Clinical outcomes and patient characteristics were taken exclusively from DEVOTE, whilst health-related quality of life utilities and UK-specific costs (expressed in 2016 GBP) were obtained from the literature. The analysis was conducted from the perspective of the National Health Service.Results: Degludec was associated with mean cost savings of GBP 28.78 per patient relative to glargine U100 in patients with type 2 diabetes at high CV risk. Cost savings were driven by the reduction in risk of diabetes-related complications with degludec, which offset the higher treatment costs relative to glargine U100. Degludec was associated with a mean improvement of 0.0064 quality-adjusted life-years (QALYs) compared with glargine U100, with improvements driven predominantly by lower rates of severe hypoglycemia with degludec versus glargine U100. Improvements in quality-adjusted life expectancy combined with cost neutrality resulted in degludec being dominant over glargine U100. Sensitivity analyses demonstrated that the incremental cost-utility ratio was stable to variations in the majority of model inputs.Conclusion: The present short-term modeling analysis found that for the basal-bolus subgroup of patients in DEVOTE, with a high risk of CV events, degludec was cost neutral (no additional costs) compared with glargine U100 over a 2-year time horizon in the UK setting. Furthermore, there were QALY gains with degludec, particularly due to the reduction in the risk of severe hypoglycemia.Funding: Novo Nordisk A/S.Trial Registration: ClinicalTrials.gov identifier, NCT01959529. [ABSTRACT FROM AUTHOR]

Introduction: Since the inception of mandatory cardiovascular (CV) safety outcome trial (CVOT) promulgated by US FDA in 2008, seven trials have so far been published with three different classes of antidiabetic drugs in type 2 diabetes mellitus (T2DM). This mini-review aims to critically analyse these CVOTs in terms of different outcomes achieved. Areas covered: An electronic search pertaining to the subject was conducted till September 2016. The three CVOT conducted with saxagliptin, alogliptin and sitagliptin respectively, found them to be CV-neutral. However, both saxagliptin and alogliptin showed an increase in hospitalization due to heart failure (hHF), while sitagliptin had no such signal. The trial conducted with empagliflozin (EMPA-REG) found it to be superior in reducing major adverse cardiac events (MACE). The CVOT conducted with lixisenatide (ELIXA) was CV-neutral, but both liraglutide (LEADER) and semaglutide (SUSTAIN-6) demonstrated superiority in reducing MACE. Expert commentary: While EMPA-REG had robust reduction in the CV-death, all-cause death and hHF, there was a discordant non-significant increase in silent myocardial infarction (MI) (assessed in approximately 50% of patients) and non-fatal stroke. LEADER had concordant reduction in all CV endpoints. SUSTAIN-6 had most robust reduction in 3P-MACE, although no reduction in the CV-death, all-cause death and hHF were observed. [ABSTRACT FROM PUBLISHER]

Recently reported cardiovascular outcome studies on empagliflozin (EMPA-REG) and liraglutide (LEADER) have spurred interest in this field of diabetology. This commentary compares and contrasts these studies with two equally important outcome trials conducted using blood pressure lowering agents. A comparison with MICROHOPE (using ramipril) and ADVANCE (using perindopril + indapamide) blood pressure arms throws up interesting facts. The degree of blood pressure lowering, dissociation between cardiovascular and cerebrovascular benefits, and discordance between renal and retinal outcomes are surprisingly similar in these trials, conducted using disparate molecules. The time taken to achieve such benefits is similar for all drugs except empagliflozin. Such discussion helps inform rational and evidence-based choice of therapy and forms the framework for future research. [ABSTRACT FROM AUTHOR]

Aims: To determine whether US and European participants in the Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results (LEADER) trial differ regarding risk factors for cardiovascular mortality and morbidity. Methods: Baseline data, stratified for prior cardiovascular disease (CVD), were compared using multivariable logistic regression analysis to establish whether region is an independent determinant of achieved targets for glycated hemoglobin (HbA1c), blood pressure (BP), and low-density lipoprotein (LDL)-cholesterol. Results: Independent of CVD history, US participants were more often of non-White origin and had a longer history of type 2 diabetes, higher body weight, and higher baseline HbA1c. They had substantially lower systolic and diastolic BP, and a marginally lower LDL-cholesterol level. Fewer US participants were diagnosed with left ventricular dysfunction. In the largest group of patients, those with prior CVD and the highest cardiovascular risk, US participants were more often female, had a higher waist circumference, and had a decreased estimated glomerular filtration rate, but less frequently prior myocardial infarction or angina pectoris. Conclusions: There were baseline differences between US and European participants. These differences may result from variation in regional targets for cardiovascular risk factor management, and should be considered in the analysis and reporting of the trial results. [ABSTRACT FROM AUTHOR]

Because macrovascular complications of diabetes are the leading cause of mortality and decreased quality of life for individuals with diabetes, prevention and risk reduction are paramount. Besides lifestyle management, contemporary therapies can significantly reduce risk for cardiovascular events in diabetes. For primary prevention, most individuals should be on statin therapy, whereas those at high atherosclerotic cardiovascular disease risk should also be on glucagon-like peptide 1 receptor agonists (GLP1RA) or sodium/glucose cotransporter-2 inhibitors (SGLT2i) at any hemoglobin A1c. For secondary prevention, addition of GLP1RA or SGLT2i, PCKS9i, rivaroxaban, and/or icosapent ethyl should be considered in addition to a statin and low-dose aspirin., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)