Sodium-glucose co-transporter-2 inhibitor cardiovascular outcome trials and generalizability to English primary care.
ABSTRACT: AIM:To identify people in English primary care with equivalent cardiovascular risk to participants in the sodium-glucose co-transporter-2 inhibitor (SGLT-2i) cardiovascular outcome trials (CVOTs). A secondary objective was to report the usage of SGLT-2is. METHODS:Cross-sectional analysis of people registered with participating practices in the Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) network on the 31 December 2016. We derived: (1) proportions of the primary care population eligible for inclusion in each SGLT-2i CVOT (CANVAS, DECLARE, EMPA-REG and VERTIS); (2) characteristics of the eligible population compared with trial participants (demographics, disease duration and vascular risk); and (3) differences within the eligible population prescribed SGLT-2is. RESULTS:The proportions of people with type 2 diabetes (N = 84 394) meeting the inclusion criteria for each CVOT were: DECLARE 27% [95% confidence interval (CI) 26.5-27.1]; CANVAS 17% (16.6-17.1); VERTIS 7% (7.1-7.4); and EMPA-REG 7% (6.5-6.8). Primary care populations fulfilling inclusion criteria were 5-8 years older than trial cohorts, and <10% with inclusion criteria of each trial were prescribed an SGLT-2i; a greater proportion were men, and of white ethnicity. CONCLUSIONS:There was variation in proportions of the primary care type 2 diabetes population fulfilling inclusion criteria of SGLT-2i CVOTs. The more stringent the inclusion criteria, the lower the proportion identified in a primary care setting. Prescription rates for SGLT-2is were low in this national database, and there were demographic disparities in prescribing.
Project description:Generalizability of findings from cardiovascular outcomes trials (CVOTs) to patients with type 2 diabetes (T2D) in clinical practice is unknown. We assessed the proportions of patients in the Diabetes Collaborative Registry who would have met enrolment criteria for pivotal CVOTs of sodium-glucose co-transporter-2 inhibitors (SGLT-2is): EMPA-REG OUTCOME, CANVAS, DECLARE and VERTIS CV. In 172 643 patients, mean [standard deviation (SD)] age and HbA1c were 68.1 (11.8) years and 7.8% (2.2), respectively; 56.8% of patients were men and SGLT-2i use was 4.4%. Atherosclerotic cardiovascular disease (ASCVD) prevalence was 64.3% and mean 10-year ASCVD risk was 28.6% in patients without ASCVD. Proportions of patients eligible for CVOTs ranged from 26% (EMPA-REG OUTCOME) to 44% (DECLARE); 48% of patients were ineligible for all CVOTs. Mean (SD) ASCVD risk was 25.4% (22.6), 32.1% (20.6) and 37.7% (19.4) in patients eligible for no, one or two CVOTs, respectively. SGLT-2i use was low in patients eligible for no CVOTs (3.5%) and at least one CVOT (5.2%). In conclusion, applicability of CVOT results to patients with T2D in clinical practice varies based on trial eligibility criteria.
Project description: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.
Project description:Objective:To assess the eligibility of patients participating in DISCOVER (a 3-year, prospective, observational study program of 15 992 patients with type 2 diabetes [T2D] initiating a second-line glucose-lowering therapy across 38 countries) for four cardiovascular outcomes trials (CVOTs) of sodium-glucose cotransporter 2 inhibitors (CANagliflozin cardioVascular Assessment Study [CANVAS], Dapagliflozin effect on CardiovascuLAR Events trial [DECLARE-TIMI 58], EMPAgliflozin cardiovascular OUTCOME event trial [EMPA-REG OUTCOME], and eValuation of ERTugliflozin effIcacy and Safety CardioVascular outcomes trial [VERTIS-CV]). Research design and methods:In this cross-sectional analysis, baseline characteristics of DISCOVER patients were compared with the inclusion and exclusion criteria of the CVOTs to assess patient eligibility, overall and in four regions (Asia-Pacific, Europe, Latin America, and Middle East and Africa). Results:Overall, 11 385 patients (71.2%) had sufficient data for the analysis; 56.1% were men. The mean age and time since T2D diagnosis were 57.4 and 5.6 years, respectively. The mean glycated hemoglobin level was 8.3%. DISCOVER patients were younger, and fewer had a history of cardiovascular disease, than those enrolled in the CVOTs. Eligibility varied across the CVOTs; the proportion of eligible DISCOVER patients was highest for DECLARE-TIMI 58 (40.5%), followed by CANVAS (19.9%), VERTIS-CV (7.2%), and EMPA-REG OUTCOME (7.1%); 54.6% of patients were not eligible for any CVOT. Eligibility for each CVOT varied across regions, which was explained by the differing proportions of patients with established cardiovascular disease. Conclusions:In a large, international population of patients with T2D initiating a second-line glucose-lowering therapy, DECLARE-TIMI 58 was the most inclusive CVOT, suggesting that its study population will be more representative of patients encountered in routine clinical practice than those of CANVAS, EMPA-REG OUTCOME, and VERTIS-CV.
Project description:BACKGROUND:Cardiovascular outcome trials of sodium-glucose co-transporter-2 inhibitors (SGLT2i CVOTs) found the agents to be associated with clinical benefits in terms of cardiovascular and renal outcomes. We performed a meta-analysis to assess and compare the overall prevalence of eligibility for the enrollment criteria of CANVAS, DECLARE-TIMI 58, EMPA-REG OUTCOME, and VERTIS-CV among unselected patients with type 2 diabetes. METHODS:This meta-analysis was registered in PROSPERO (CRD42020172032). PubMed, CENTRAL, Scopus and Web of Science were researched in March 2020. Studies evaluating the prevalence of eligibility for each SGLT2i CVOT were selected. Endpoints were estimated using a random-effects model. RESULTS:Five studies, evaluating 1,703,519 patients with type 2 diabetes, were included. Overall, the prevalence of eligible patients according to the enrollment criteria of CANVAS, DECLARE-TIMI 58, EMPA-REG OUTCOME, and VERTIS-CV was 36.4%, 49.5%, 17.0% and 19.0%, respectively. In head-to-head comparisons, DECLARE-TIMI 58 was associated with the highest odds of eligibility (1.74 versus CANVAS, 5.15 versus EMPA-REG OUTCOME and 4.81 versus VERTIS-CV), followed by CANVAS and EMPA-REG OUTCOME/VERTIS-CV. A high heterogeneity was found for all the outcomes. CONCLUSIONS:The present review showed that a considerable number of patients counseled in clinical practice could have been eligible for SGLT2i CVOTs. Particularly, dapagliflozin was shown to be the SGLT2i with the largest generalizability of findings from its CVOT according to the odds ratio of eligibility for the enrollment criteria among unselected patients with type 2 diabetes. Further country- or region-specific studies are needed to confirm the applicability of our results.
Project description:INTRODUCTION:Sodium-glucose co-transporter-2 (SGLT2) inhibitors are oral antihyperglycemic agents for the treatment of people with type 2 diabetes (T2DM). Two recent cardiovascular outcome trials (CVOTs), the EMPA-REG OUTCOME trial and CANVAS Program, have demonstrated that SGLT2 inhibitors have cardiovascular benefit in high-risk cardiovascular patients. The aim of our study will be to identify the prevalence of patients in an English primary care setting with the equivalent cardiovascular risk profile to those included in each of four SGLT2 inhibitor CVOTs: CANVAS, DECLARE, EMPA-REG, and VERTIS CV. METHODS:Routinely collected primary care data from the Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) network database will be used. We will perform a cross-sectional analysis to calculate the prevalence of people that have equivalent cardiovascular risk to participants included in each of the four above-mentioned SGLT2 inhibitor CVOTs. The demographic and clinical characteristics of the subgroups will also be compared with participants in each trial. The study cohort will include people with T2DM in the RCGP RSC dataset. Subgroups of people will be identified using Read codes that most closely match the inclusion criteria of each trial. Descriptive statistics will be used to report the characteristics of people at high cardiovascular risk and compared against those of people in each CVOT. PLANNED OUTPUTS:Findings from the study will be submitted for publication in a peer-reviewed journal to report the applicability of each SGLT2 inhibitor trial to real-world clinical practice. FUNDING:AstraZeneca UK Limited.
Project description:Objective:Regulatory agencies require the assessment of cardiovascular (CV) safety for new type 2 diabetes (T2D) therapies through CV outcome trials (CVOTs). However, patients included in CVOTs assessing sodium-glucose cotransporter-2 inhibitors (SGLT2i) might not be representative of those seen in clinical practice. This study examined the proportion of patients that would have been enrolled into three main SGLT2i CVOTs to determine whether these trials' eligibility criteria can be applied to a real-world Mediterranean T2D population. Methods:Cross-sectional, retrospective, cohort study of T2D patients registered in primary care centres of the Catalan Institute of Health using medical records from a population database (SIDIAP) that includes approximately 74% of the population in Catalonia (Spain). Eligibility criteria were according to those of three SGLT2i CVOTs: EMPA-REG OUTCOME (empagliflozin), CANVAS (canagliflozin), and DECLARE-TIMI 58 (dapagliflozin). Results:By the end of 2016, the database included 373,185 patients with T2D with a mean age of 70 ± 12 years, 54.9% male, with a mean duration of T2D of 9 ± 6 years, and a mean glycated haemoglobin (HbA1c) of 7.12% ± 1.32 (59% with HbA1c < 7%). Of these, 86,534 (23%) had established CV disease and 28% chronic renal failure (estimated glomerular filtration < 60?ml/min/1.73m2). Among all included patients, only 8.2% would have qualified for enrolment into the EMPA-REG OUTCOME trial, 29.6% into the CANVAS program, and 38% into the DECLARE-TIMI 58 trial. The main limiting factors for inclusion would have been a previous history of CV disease and the baseline HbA1c value. Conclusion:The external validity of the analysed CVOTs is clearly limited when applying the same eligibility criteria to a T2D Mediterranean population.
Project description:Diabetes-related complications including cardiovascular disease, heart failure (HF), chronic kidney disease, retinopathy, and neuropathy are associated with a high burden of disease. Early initiation of glucose-lowering therapy in patients with type 2 diabetes to achieve glycemic control is important for reduction of not only microvascular risk but also of CV (cardiovascular) risk. Clinical studies have indicated that early achievement of glycemic targets is likely to have the greatest effect on preventing microvascular and macrovascular complications. In addition to improvements in glycemic control and CV risk factors, CV outcomes trials (CVOTs) of empagliflozin (EMPA-REG OUTCOME), canagliflozin (CANVAS), and dapagliflozin (DECLARE-TIMI 58) showed significant glucose-independent reductions in the risk of major adverse CV events and/or hospitalization for HF, as well as reductions in the risk of kidney disease progression, versus placebo. These CVOTs and a renal outcomes study of canagliflozin (CREDENCE) support the early initiation of sodium-glucose cotransporter (SGLT)-2 inhibitors to potentially provide the most benefit toward glycemic control and CV and renal risk. Thus, current treatment recommendations include the early addition of SGLT-2 inhibitor therapy, not only in patients with established CVD, HF, and/or CKD but also in the general population of patients with T2D.Funding: AstraZeneca.
Project description:BACKGROUND:For patients with type 2 diabetes (T2D), cardiovascular disease (CVD) is the single most common cause of mortality. In 2008 and 2012, the Federal Drug Administration (FDA) and the European Medicines Agency (EMA) respectively mandated cardiovascular outcomes trials (CVOTs) on all new anti-diabetic agents, as prospective trials statistically powered to rule out excess cardiovascular risk in patients with T2D. Unexpectedly, some of these CVOTs have demonstrated not only cardiovascular safety, but also cardioprotective effects, as was first shown for the SGLT2 inhibitor empagliflozin in EMPA-REG OUTCOME. EXPERT OPINION:To debate newly available CVOT data and to put them into context, we convened as a group of medical experts from the Central and Eastern European Region. Here we describe our discussions, focusing on the conclusions we can draw from EMPA-REG OUTCOME and other SGLT2 inhibitor CVOTs, including when considered alongside real-world evidence. CONCLUSION:CVOTs investigating SGLT2 inhibitors have suggested benefits beyond glucose lowering that have been confirmed in real-world evidence studies.
Project description:Recently, two large randomized controlled trials which only included patients with underlying cardiovascular disease (CVD) or patients at high risk for CVD showed that two sodium glucose co-transporter 2 inhibitors (SGLT-2is) significantly reduced hospitalization for heart failure (hHF), with an early separation in the survival curves for hHF. There were concerns whether SGLT-2i use could protect hHF in patients without CVD and how soon SGLT-2i-treated patients show a lower risk of hHF. Thus, we aimed to evaluate whether the heart failure protective effect of SGLT-2i differs depending on the underlying CVD and the prescription period compared with dipeptidyl peptidase-4 inhibitors (DPP-4i).We performed a nationwide retrospective observational study to estimate the effect of SGLT-2i on HF. The 59,479 SGLT-2i new-users were matched with same number of DPP-4i new-users through propensity score matching using 53 confounding variables. Kaplan-Meier (K-M) curves and Cox proportional hazards regression analyses were used to estimate the risk of hospitalization for hHF.The incidence rates of hHF were 0.83 and 1.13 per 100 person-years in SGLT-2i-treated patients and DPP-4i-treated patients, respectively. The hazard ratios of hHF were 0.66 (95% confidence interval 0.58-0.75) in SGLT-2i-treated patients compared with the DPP-4i-treated patients. Among the patients with underlying CVD, SGLT-2i-treated patients were associated with a lower risk of hHF from 30 days to 3 years after initiating drugs compared with DPP-4i. However, SGLT-2i use only showed a lower risk of hHF with a significant difference 3 years after drug initiation among patients without underlying CVD.Our findings suggest that SGLT-2i reduced hHF compared with DPP-4i. A heart failure protective effect of SGLT-2i use vs. DPP-4i use was shown 30 days after initiating the SGLT-2i among patients with established CVD, but this effect appeared later in patients without established CVD.
Project description:The 5th Cardiovascular Outcome Trial (CVOT) Summit was held in Munich on October 24th-25th, 2019. As in previous years, this summit served as a reference meeting for in-depth discussions on the topic of recently completed and presented CVOTs. This year, focus was placed on the CVOTs CAROLINA, CREDENCE, DAPA-HF, REWIND, and PIONEER-6. Trial implications for diabetes management and the impact on new treatment algorithms were highlighted for diabetologists, cardiologists, endocrinologists, nephrologists, and general practitioners. Discussions evolved from CVOTs to additional therapy options for heart failure (ARNI), knowledge gained for the treatment and prevention of heart failure and diabetic kidney disease in populations with and without diabetes, particularly using SGLT-2 inhibitors and GLP-1 receptor agonists. Furthermore, the ever increasing impact of CVOTs and substances tested for primary prevention and primary care was discussed. The 6th Cardiovascular Outcome Trial Summit will be held in Munich on October 29th-30th, 2020 (https://www.cvot.org).