Sodium-Glucose Co-transporter 2 (SGLT2) Inhibitor: Comparing Trial Data and Real-World Use

Abstract

IntroductionThe first cardiovascular safety trial in the sodium-glucose co-transporter-2 (SGLT2) inhibitor drug class, the Empagliflozin Cardiovascular Outcomes and Mortality in Type 2 Diabetes (EMPA-REG OUTCOME) trial, demonstrated significant cardiovascular risk reduction with empagliflozin. It is currently not clear what proportions of people with type 2 diabetes (T2DM) have the same high cardiovascular risk as those included in the trial, and will therefore be likely to experience the same cardiovascular benefit. We aimed to identify and describe the proportion of people with T2DM from a representative English national population who have the comparable high cardiovascular risk to those included in the EMPA-REG trial.MethodA cross-sectional analysis of cardiovascular risk in people with T2DM and a subgroup prescribed SGLT2 inhibitors. Patients were identified from the Royal College of General Practitioners Research and Surveillance Centre database. Cardiovascular risk factors were identified from electronic patient records.ResultsFrom 1,238,909 patients at 128 GP practices, we identified 60,327 adults with T2DM (mean age 66.1 years, SD 13.9) of whom 55.6% were male. From these 1642 (2.7%) people had been initiated on an SGLT2 inhibitor (mean age 58.1 years, SD 10.4; 58.8% male). In the complete T2DM group only 15.7% (95% CI 15.5–16.0%) had the same high cardiovascular risk as those included in the EMPA-REG trial. In those already initiated on SGLT2 inhibitors this proportion was 11.1% (95% CI 9.8–12.4%). Whilst the proportion was higher in the oldest age groups, in those 70+ years old less than a quarter met the EMPA-REG trial high cardiovascular risk criteria.ConclusionsThe EMPA-REG trial results are applicable only to a small proportion of people with T2DM and a smaller proportion of those currently treated with SGLT2 inhibitors. Additional data are required to identify any cardiovascular benefit in people with lower cardiovascular risk.FundingAstraZeneca.Electronic supplementary materialThe online version of this article (doi:10.1007/s13300-017-0254-7) contains supplementary material, which is available to authorized users.

Real‐world prevalence of the inclusion criteria for the LEADER trial: Data from a national general practice network

“…A study assessing the EMPA-REG CVOT inclusion criteria against the RCGP RSC cohort database reported that the inclusion criteria are applicable only to a small proportion of people with type 2 diabetes (15.7% of the total type 2 diabetes population), and that an even smaller proportion of those who are currently treated with SGLT2 inhibitors have the same high CV risk as that of the EMPA-REG trial population (11.1% of the total type 2 diabetes population), thus calling into question whether this class of drug is also being used to its potential, at least in England. 42 In addition, as the pre-approval CVOT SUSTAIN 6 shares identical inclusion criteria to LEADER, 15 the same RCGP RSC-CVD cohort would be identified as in the present study, and may also benefit from the use of the once-weekly GLP-1RA semaglutide, when this is launched in the United Kingdom.…”

“…While it could be argued that the slow uptake of GLP‐1RAs may be attributable to the reluctance of physicians to initiate injectable treatments in their patients with type 2 diabetes, analogous studies with oral glucose‐lowering treatments with proven CV benefits, such as the SGLT2 inhibitor empagliflozin, showed a similar pattern to that observed with GLP‐1RAs. A study assessing the EMPA‐REG CVOT inclusion criteria against the RCGP RSC cohort database reported that the inclusion criteria are applicable only to a small proportion of people with type 2 diabetes (15.7% of the total type 2 diabetes population), and that an even smaller proportion of those who are currently treated with SGLT2 inhibitors have the same high CV risk as that of the EMPA‐REG trial population (11.1% of the total type 2 diabetes population), thus calling into question whether this class of drug is also being used to its potential, at least in England …”

What have we learnt from “real world” data, observational studies and meta‐analyses

“…Participants of clinical trials, enrolled following assessment of strict inclusion and exclusion criteria, tend to be more interested in their disease and have greater motivation to attend appointments, take prescribed medication and report adverse events. Real world data can be obtained from a number of sources for example electronic health records provide patient‐level outcomes and disease‐specific symptoms and treatments, health surveys give indicators of health status, healthcare utilization and treatment patterns . Claims databases provide administrative data, diagnoses, procedures and costs and patient registries are a source of observational data and specified outcomes in a defined population.…”

“…Real world data can be obtained from a number of sources for example electronic health records provide patientlevel outcomes and disease-specific symptoms and treatments, health surveys give indicators of health status, healthcare utilization and treatment patterns. 37 Claims databases provide administrative data, diagnoses, procedures and costs and patient registries are a source of observational data and specified outcomes in a defined population.…”

When metformin is not enough: Pros and cons of SGLT2 and DPP‐4 inhibitors as a second line therapy

“…However, the EMPA‐REG OUTCOME trial population was at very high risk for cardiovascular events, and therefore, the applicability to a broader real world population is unclear. Indeed, only 11% of people in the real world currently using SGLT2 inhibitors had similar cardiovascular risk, glycaemic control, and renal function to the trial participants . The Canagliflozin Cardiovascular Assessment Study (CANVAS) trial program with canagliflozin has also demonstrated a similar cardiovascular benefit to the EMPA‐REG OUTCOME trial but in a slightly lower risk population (Table ) .…”