Generalizability of Cardiovascular Safety Trials on SGLT2 Inhibitors to the Real World: Implications for Clinical Practice

Aim To assess the unrealized potential of glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) or sodium‐glucose co‐transport‐2 inhibitor (SGLT2i) use to reduce mortality in veterans with type 2 diabetes (T2D), coronary artery disease (CAD), and other characteristics congruent with clinical trial cohorts that established the efficacy of these agents. Methods Veterans with T2D and CAD on angiography in 2014 who were untreated with either a GLP‐1RA or a SGLT2i were assessed for key eligibility criteria of the LEADER (GLP‐1RA) and EMPA‐REG OUTCOME (SGLT2i) trials. Trial hazard ratios and 95% confidence intervals for all‐cause death were applied to deaths observed in veterans through 2018 to estimate the potential benefit of GLP‐1RA or SGLT2i use. Results Median observation was 4.3 years. Of 15 987 veterans with T2D and CAD, 1186 (7.4%) were excluded for GLP‐1RA or SGLT2i treatment, and 1386 lacked glycated haemoglobin measurement. Of the remaining 13 415 patients, 4103 (30.1%) and 5313 (39.6%) fulfilled the key criteria for the LEADER and EMPA‐REG OUTCOME trials, respectively. Death occurred in 1009 (24.6%) of LEADER‐eligible patients and 1335 (25.1%) of EMPA‐REG OUTCOME‐eligible patients. Under treatment with liraglutide in LEADER‐eligible veterans, a 3.5% (0.7%‐6.2%) potential absolute mortality reduction, corresponding to 144 (28‐253) fewer deaths (0.88 [0.17‐1.56] per 100 person‐years), might have been expected. Similarly, under treatment with empagliflozin in EMPA‐REG OUTCOME‐eligible veterans, a 7.9% (4.5%‐10.8%) potential absolute mortality reduction, corresponding to 418 (230‐573) fewer deaths (1.98 [1.14‐2.72] per 100 person‐years), might have been expected. Conclusions This analysis indicates unrealized opportunities to reduce mortality in selected veterans with T2D and CAD via increased GLP‐1RA and SGLT2i use.

Section: Discussionsupporting

confidence: 80%

Potential unrealized mortality benefit of glucagon‐like peptide‐1 receptor agonists and sodium‐glucose co‐transport‐2 inhibitors: A report from the Veterans Health Administration Clinical Assessment, Reporting and Tracking program

Salahuddin

Richardson

McNeal

et al. 2020

“…Similar analyses have been performed on CVOTs for SGLT‐2is . Nicolucci et al 11 showed that real‐world T2D patients eligible for CVOTs on SGLT‐2is were different to trial populations in many instances . To date, however, no study has been able to calculate what proportion of real‐world patients truly constitute CVOT‐like populations.…”

Section: Discussionmentioning

confidence: 91%

“…A few studies have examined what proportion of T2D patients from various clinical care settings would satisfy I/E criteria to be enrolled in specific CVOTs, but no study to date has examined what the proportion is of real‐world patients that corresponds to CVOT populations. Indeed, applying CVOT enrolment criteria to real‐world T2D patients yields subgroups that are substantially different from the actual CVOT populations, thereby leaving the question of generalizability unanswered.…”

Section: Introductionmentioning

confidence: 99%

Enrolment criteria for diabetes cardiovascular outcome trials do not inform on generalizability to clinical practice: The case of glucagon‐like peptide‐1 receptor agonists

Sciannameo

Berchialla

Orsi

et al. 2020

Aim: To evaluate the generalizability of cardiovascular outcome trials (CVOTs) on glucagon-like peptide-1 receptor agonists (GLP-1RAs), we assessed what proportion of real-world patients with type 2 diabetes (T2D) constitute true CVOT-like populations. Materials and Methods: We applied inclusion/exclusion (I/E) criteria of each GLP-1RA CVOT to a cross-sectional database of 281 380 T2D patients from Italian diabetes outpatient clinics. We calculated the proportion of patients eligible for each CVOT and compared their clinical characteristics with those of trial patients. In addition, we used a Bayesian network-based method to sample the greatest subsets of real-world patients yielding true CVOT-like populations.Results: Between 98 725 and 124 164 T2D patients could be evaluated for CVOT eligibility. After excluding patients who were already on GLP-1RAs and applying I/E criteria, 35.8% of patients would be eligible for REWIND, 34.1% for PIONEER-6, 13.4% for EXSCEL, 10.1% for SUSTAIN-6, 9.5% for HARMONY and 9.4% for LEADER. Overall, 45.4% of patients could be eligible for at least one of the CVOTs.These patients, however, were extremely different to trial patients in most of the clinical characteristics, including demographics, concomitant medications and complications. The greatest CVOT-like subsets of real-world patients were 0.5% for SUSTAIN-6, 1.0% for EXSCEL, 1.2% for LEADER, 1.8% for PIONEER-6 and 7.9% for REWIND. Conclusions:A very small proportion of real-world patients constitute true CVOTlike populations. These findings question whether any meaningful information can be drawn from applying trial enrolment criteria to real-world T2D patients. K E Y W O R D S cardiovascular disease, glucagon-like peptide-1 analogue, pharmaco-epidemiology, population study, type 2 diabetes

“…“Real‐life” use of new cardioprotective GLDs in patients with T2DM and established CVD in routine clinical care has been sparsely investigated 20–24 . Whether results of the recent large cardiovascular outcome trials have had an impact on the use of cardioprotective GLDs is unknown.…”

Section: Introductionmentioning

confidence: 99%

Real‐world use of cardioprotective glucose‐lowering drugs in patients with type 2 diabetes and cardiovascular disease: A Danish nationwide cohort study, 2012 to 2019

Funck

Knudsen

Hansen

et al. 2020

Aims To investigate temporal trends in time to initiation of sodium‐glucose co‐transporter‐2 inhibitors and glucagon‐like peptide 1 analogues (cardioprotective glucose‐lowering drugs [GLDs]) in patients with a new dual diagnosis of type 2 diabetes (T2DM) and cardiovascular disease (CVD). Materials and methods In a cohort study, we identified patients with a new dual diagnosis of T2DM and CVD using linked healthcare data from nationwide registries on drug prescriptions and diagnosis codes. For each calendar year between 2012 and 2018, we examined time to initiation and cumulative user proportions (CUPs) for cardioprotective GLD use 1 and 2 years after the dual diagnosis. Results Among all individuals living in Denmark in the period 2012 to 2018, 41 733 patients with a new dual diagnosis of T2DM and CVD were identified (median [interquartile range] age 71 [64–79] years, 61% male, and 57% with CVD as the latest diagnosis). Incidence curve slopes and 1‐ and 2‐year CUPs for cardioprotective GLDs increased during the study period (1‐year CUP 4.0%, 95% confidence interval [CI] 3.6–4.5) in 2012 to 14.7, 95% CI 13.7–15.7, in 2018; 2‐year CUP 5.5, 95% CI 5.0–6.1, in 2012 to 16.7, 95% CI 15.8–17.7, in 2017). T2DM patients with CVD as the second (latest) diagnosis had higher 1‐year CUPs than CVD patients with T2DM as the latest diagnosis: 2012: 7.0 (95% CI 6.2–8.0) versus 1.4 (95% CI 1.0–1.8); 2018: 18.1 (95% CI 16.8–19.6) versus 10.0 (95% CI 8.8‐11.3). Conclusions In patients with T2DM and CVD, the incidence of cardioprotective GLD initiation increased between 2012 and 2018, however, within 2 years of dual diagnosis, it remained low.