The representativeness of eligible patients in type 2 diabetes trials: a case study using GIST 2.0

Sen, A. K.; Goldstein, Andrew; Chakrabarti, Shreya; Shang, Ning; Kang, Tian; Yaman, Anil; Ryan, Patrick B.; Weng, Chunhua

doi:10.1093/jamia/ocx091

Cited by 17 publications

(21 citation statements)

References 35 publications

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“…The choice of CV inclusion criteria in CVOTs therefore predefines the trial‐specific baseline CV risk, thereby impacting the representativeness of the trial population compared to a general T2D population . This difference is important, as people with T2D who have, for example, a high CV risk may respond differently to the intervention compared with those with low CV risk, potentially challenging the external validity of results when comparing a trial population with a general T2D population …”

Section: Inroductionmentioning

confidence: 99%

“…7 This difference is important, as people with T2D who have, for example, a high CV risk may respond differently to the intervention compared with those with low CV risk, potentially challenging the external validity of results when comparing a trial population with a general T2D population. 23,24 We present a novel way of evaluating the external validity of CVOT results (DECLARE-TIMI 58) in an observational setting, by both using similar main CV inclusion criteria to define a population (DECLARE-likepopulation), and by assessing identical trial-specific outcomes (HHF or CV mortality, and major adverse CV events [MACE]). 5 To our knowledge, no observational study assessing an SGLT2 inhibitor and its associations with CV risk has previously investigated the external validity of CVOT results by applying the same CV inclusion criteria to a general T2D population and assessing identical outcomes.…”

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confidence: 99%

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Dapagliflozin and cardiovascular mortality and disease outcomes in a population with type 2 diabetes similar to that of the DECLARE‐TIMI 58 trial: A nationwide observational study

Norhammar

Bodegård

Nyström

et al. 2019

Diabetes Obesity Metabolism

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Aims To investigate cardiovascular (CV) safety and event rates for dapagliflozin versus other glucose‐lowering drugs (GLDs) in a real‐world type 2 diabetes population after applying the main inclusion criteria and outcomes from the DECLARE‐TIMI 58 study. Methods Patients with new initiation of dapagliflozin and/or other GLDs were identified in Swedish nationwide healthcare registries for the period 2013 to 2016. Patients were included if they met the main DECLARE‐TIMI 58 inclusion criteria: age ≥40 years and established CV disease or presence of multiple‐risk factors, e.g. men aged ≥55 years and women aged ≥60 years with hypertension or dyslipidaemia. Propensity scores for the likelihood of dapagliflozin initiation were calculated, then 1:3 matching was carried out. DECLARE‐TIMI 58 outcomes were hospitalization for heart failure (HHF) or CV‐specific mortality, and major adverse CV events (MACE; CV‐specific mortality, myocardial infarction, or stroke). Cox survival models were used to estimate hazard ratios (HRs). Results After matching, a total of 28 408 new‐users of dapagliflozin and/or other GLDs were identified, forming the population for the present study (henceforth referred to as the DECLARE‐like cohort. The mean age of this cohort was 66 years, and 34% had established CV disease. Dapagliflozin was associated with 21% lower risk of HHF or CV mortality versus other GLDs (HR 0.79, 95% confidence interval [CI] 0.69‐0.92) and had no significant association with MACE (HR 0.90, 95% CI 0.79‐1.03). HHF and CV mortality risks, separately, were lower at HR 0.79 (95% CI 0.67‐0.93) and HR 0.75 (95% CI 0.57‐0.97), respectively. Non‐significant associations were seen for myocardial infarction and stroke: HR 0.91 (95% CI 0.74‐1.11) and HR 1.06 (95% CI 0.87‐1.30), respectively. Conclusion In a real‐world population similar to those included in the DECLARE‐TIMI 58 study, dapagliflozin was safe with regard to CV outcomes and resulted in lower event rates of HHF and CV mortality versus other GLDs.

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Section: Inroductionmentioning

confidence: 99%

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confidence: 99%

Dapagliflozin and cardiovascular mortality and disease outcomes in a population with type 2 diabetes similar to that of the DECLARE‐TIMI 58 trial: A nationwide observational study

Norhammar

Bodegård

Nyström

et al. 2019

Diabetes Obesity Metabolism

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“…Many CVOTs include patients with a high risk of CV and with an expected high rate of CV events, to ensure that differences in CV outcomes may be reported with sufficient statistical power. As a consequence, various degrees of strict CVOT patient enrolment criteria may impact the representativeness of the trial population of a general T2D population and, thus, may also impact the external validity of study results …”

Section: Introductionmentioning

confidence: 99%

“…As a consequence, various degrees of strict CVOT patient enrolment criteria may impact the representativeness of the trial population of a general T2D population and, thus, may also impact the external validity of study results. 8,9 Four CVOTs that examined treatment with SGLT-2is are within the scope of this study. [3][4][5][6] Major differences exist among these CVOTs concerning inclusion criteria.…”

Section: Introductionmentioning

confidence: 99%

How representative of a general type 2 diabetes population are patients included in cardiovascular outcome trials with SGLT2 inhibitors? A large European observational study

Birkeland

Bodegård

Norhammar

et al. 2019

Diabetes Obesity Metabolism

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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.

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“…For instance, in a previous literature review, the external validity of large trials assessing the impact of glycaemic control on CVD in patients with T2D was reported as limited when applied to a T2D population-based cohort [27]. Another recent study evaluated the population representativeness of 1691 registered T2D trials [28] and found that in 51.4% of cases (and 53.1% of phase 2 and 3 interventional trials), the population representativeness was <5%. Of note, and in line with our results, the eligibility criterion that had the largest effect on the population representativeness was HbA1c [28].…”

Section: Discussionmentioning

confidence: 99%

How Many Patients with Type 2 Diabetes Meet the Inclusion Criteria of the Cardiovascular Outcome Trials with SGLT2 Inhibitors? Estimations from a Population Database in a Mediterranean Area

Canivell

Mata-Cases

Vlacho

et al. 2019

Journal of Diabetes Research

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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.

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The representativeness of eligible patients in type 2 diabetes trials: a case study using GIST 2.0

Cited by 17 publications

References 35 publications

Dapagliflozin and cardiovascular mortality and disease outcomes in a population with type 2 diabetes similar to that of the DECLARE‐TIMI 58 trial: A nationwide observational study

Dapagliflozin and cardiovascular mortality and disease outcomes in a population with type 2 diabetes similar to that of the DECLARE‐TIMI 58 trial: A nationwide observational study

How representative of a general type 2 diabetes population are patients included in cardiovascular outcome trials with SGLT2 inhibitors? A large European observational study

How Many Patients with Type 2 Diabetes Meet the Inclusion Criteria of the Cardiovascular Outcome Trials with SGLT2 Inhibitors? Estimations from a Population Database in a Mediterranean Area

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