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Clinical trials in type 2 diabetes mellitus (T2DM) often provide limited insights on cardiovascular (CV) outcomes, in part due to limitations on trial designs and study populations. Real-world data narrow these knowledge gaps, validate trial findings and inform changes to clinical practice. At the 2018 American College of Cardiology Annual Scientific Session and Expo, Dr Mikhail Kosiborod of the University of Missouri-Kansas City, US, reported findings from the CVD-REAL (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors) 2 trial, which built upon the results of the CVD-REAL study and highlighted the real-world impact of sodium-glucose cotransporter-2 (SGLT-2) inhibitors on CV outcomes.
Various trials have demonstrated lowered risk of CV events in patients with T2DM taking SGLT-2 inhibitors. Notably, landmark trials with canagliflozin and empagliflozin have shown significant reductions in the composite endpoint of deaths from CV causes, nonfatal MI and nonfatal stroke among patients with high CV risk. [N Engl J Med2017; 377: 644 - 657; N Engl J Med 2015; 373: 2117 - 2128]
The CVD-REAL trial was an international pharmaco-epidemiologic study that assessed rates of hospitalization due to heart failure (HHF) and death in 309,056 patients with T2DM with and without established CV disease. These patients, who were propensity-matched prior to inclusion, were newly initiated on either an SGLT-2 inhibitor or other glucose-lowering drugs (GLDs). Patient data were collected from medical claims, primary care/hospital records and registries from the US, Norway, Denmark, Sweden, Germany and the UK. [Circulation 2017; 136: 249 - 259]
Among the 154,528 patients given SGLT-2 inhibitors, canagliflozin, dapagliflozin and empagliflozin accounted for 53 percent, 42 percent and 5 percent of treatment exposure time, respectively, with rates varying between countries. Investigators reported that compared with other GLDs, SGLT-2 inhibitors significantly lowered the measured parameters, with no significant heterogeneity by country. (Table 1)
With findings consistent with results of empagliflozin鈥檚 CV outcome trial, the investigators concluded that these CV benefits might be a class effect.
The follow-up CVD-REAL Nordic study focused on evaluating the impact of newly prescribed SGLT-2 inhibitors on CV mortality and morbidity using population-level registries in Denmark, Norway and Germany. Patients enrolled in this study had a broad CV risk profile, with 25 percent having established CV disease. Total exposure time during the study period was 94 percent for dapagliflozin, 5 percent for empagliflozin and 1 percent for canagliflozin. Patients were well balanced at baseline following propensity matching: 22,830 were on SGLT-2 inhibitors and 68,490 were on other GLDs. [Lancet Diabetes Endocrinol 2017; 15: 709 - 717]
Results showed CV risk reduction with SGLT-2 inhibitors vs other GLDs. (Table 2) There were no significant differences for the parameters of nonfatal MI, nonfatal stroke and atrial fibrillation.
鈥淗owever, the CVD-REAL and CVD-REAL Nordic results had limited relevance on a global level. A majority of patients with T2DM live in the Asia-Pacific region and the Middle East, and are not limited to North America and Europe,鈥?said Kosiborod. [International Diabetes Federation Diabetes Atlas: 8th edition, 2017] 鈥淭hese patients have different characteristics, treatment patterns and CV outcomes compared with their Western counterparts. For instance, stoke is more common in Asia that in the West.鈥?[Circulation 2008; 118: 2702 - 2709]
CVD-REAL 2: A global population
The CVD-REAL 2 study focused on a broad range of CV outcomes
based on broad patient data from Asia-Pacific (Australia, Japan,
Singapore and South Korea), the Middle East (Israel) and North America
(Canada). Patients were aged 鈮?8 years and had established T2DM with
more than a year鈥檚 historical data. Patients with type 1 or gestational
diabetes were excluded from the analysis. [J Am Coll Cardiol 2018; pii: S0735 - 1097(18)33528-9]
The investigators evaluated the CV outcomes of all-cause death, HHF, all-cause death or HHF, MI and stroke in 408,807 patients with a total of 470,128 episodes of initiation of an SGLT-2 inhibitor (n=235,064) or other GLD (n=235,064). Propensity-matching produced a well-balanced cohort with a mean age of 57 years. Around a quarter of patients in both arms had established CV disease. Slightly over 60 percent of patients in both arms were on antihypertensive therapies, primarily angiotensin II receptor blockers (47 percent) or angiotensin-converting enzyme inhibitors (9 percent). In addition, around 75 percent of the patients were on metformin, and approximately half were on dipeptidyl peptidase-4 inhibitors and sulphonylureas. A further 65 percent of the patients were on statins.
鈥淭he SGLT-2 inhibitor exposure time varied between different country populations,鈥?noted Kosiborod. 鈥淒apagliflozin made up the majority of SGLT-2 inhibitor use in this study, accounting for 75 percent of exposure time, followed by empagliflozin [9 percent], ipragliflozin [which was available in South Korea and Japan only] [8 percent], and canagliflozin [4 percent].鈥?/p>
The CVD-REAL 2 study reported on more than 1 year of patient follow-up with nearly 500,000 patient-years, and nearly 10,000 composite events for HHF or all-cause death.
Results demonstrated significant reductions in the risk of all
study endpoints, namely all-cause death (hazard ratio [HR], 0.51; P<0.001), HHF (HR, 0.64; P=0.001) and the composite of all-cause
death or HHF (HR, 0.60, P<0.001) with SGLT-2 inhibitors vs other
The CV benefits with SGLT-2 inhibitors were also shown to extend across ethnicity, geographic regions and presence or absence of CV disease at baseline.
鈥淯nlike the earlier trials, CVD-REAL 2 demonstrated that real-world initiation of SGLT-2 inhibitors led to a significant 19 percent reduction in the risk of MI and a 32 percent reduction in the risk of stroke vs other GLDs,鈥?Kosiborod pointed out. (Figure) These findings were particularly notable because previous CV outcome trials of empagliflozin and canagliflozin failed to demonstrate significant benefits in these two parameters. [N Engl J Med2017; 377: 644 - 657; N Engl J Med 2015; 373: 2117 - 2128]
Overall, benefits gained through SGLT-2 inhibitor treatment were comparable between patients with and without prior CV disease.
鈥淚n conclusion, CVD-REAL 2 established that SGLT-2 inhibitors produced a class effect to lower CV events, including MI and stroke, in a broader patient population,鈥?said Kosiborod.
Ongoing DECLARE-TIMI 58 trial
The ongoing DECLARE (Design and Rationale for the Dapagliflozin Effect on Cardiovascular Events)鈥揟IMI 58 trial is a phase IIIb, global, randomized, double-blind, placebo-controlled trial designed to evaluate the CV safety and efficacy of dapagliflozin. The trial included patients with T2DM who have either established atherosclerotic CV disease (ASCVD) (40 percent of the cohort) or multiple CV risk factors for ASCVD (60 percent).
Patients were randomized to receive either dapagliflozin 10 mg or matched placebo. The primary safety outcome was time to the first major adverse CV event (composite of CV death, MI or ischaemic stroke). The coprimary efficacy outcomes included the composite of CV death, MI or ischaemic stroke, as well as the composite of CV death or HHF, which is a clinically relevant endpoint that was not evaluated in previous CV outcome trials of SGLT-2 inhibitors.
The study aims to prove the efficacy and safety of dapagliflozin in reducing the event rate of major CV events.
This special report is made possible through an unrestricted educational grant from the industry.