In more than 300,000 type 2 diabetes patients across the US and Europe, the first wave of the CVD-REAL (Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors) study has previously demonstrated the cardiovascular (CV) benefits of the sodium-glucose co-transporter 2 (SGLT2) inhibitors.1 Deemed to be an ‘elegant epidemiological investigation’,2 the second wave of this multinational, observational cohort study (CVD-REAL 2) now provides further evidence for the CV benefits of SGLT2 inhibitors in the predominantly Asian patient population. The impressive results were presented at the American College of Cardiology (ACC) 2018 Annual Scientific Session and simultaneously published in the Journal of the American College of Cardiology.3-5
An elegant epidemiological investigation
One of the more exciting aspects in SGLT2 inhibition is the potential cardioprotective effects. Positive results from large CV outcomes trials of SGLT2 inhibitors in patients with established CV disease, such as the EMPA-REG OUTCOME and the CANVAS Program, have generated initial excitement.1,5 Nonetheless, the results of these trials may not be directly relevant to real-world practice, particularly in a broad population of type 2 diabetes patients without CV disease.1,5
It is therefore reassuring to see that the heart failure and mortality findings in the first wave of CVD-REAL study were ‘remarkably similar’ to those observed in the EMPA-REG OUTCOME.1,6 “Since studying such a low risk population in a randomized clinical trial may not be feasible, investigations such as CVD-REAL, may provide the only available data in regards to SGLT2 inhibition effects for very low risk patients,” the CVD-REAL 2 investigators wrote.5
Describing the rationale for CVD-REAL 2, lead author Dr. Mikhail Kosiborod of Saint Luke’s Mid America Heart Institute and University of Missouri-Kansas City, US, noted that most people with type 2 diabetes live outside the US and Europe.7 In Asia-Pacific and the Middle East, “there are important differences in patient characteristics, treatment patterns, and types of cardiovascular events experienced by patients in these regions,” he said.7
CVD-REAL 2 assessed claims, medical records, and national registries in six countries (Figure 1),8 with a much more diverse patient population as compared to the first wave of CVD-REAL, both geographically and ethnically.5
Databases included in CVD-REAL 2 were: National Health Insurance Service (NHIS) in South Korea, Medical Data Vision Co., Ltd (MDV) in Japan, SingHealth Diabetes Registry (SDR) in Singapore, Maccabi Health Management Organization (HMO) in Israel, National Diabetes Services Scheme (NDSS) in Australia, and MCHP Population Health Research Data Repository in Canada.5
The investigators identified 3.9 million initiation episodes of SGLT2 inhibitors or other glucose lowering drugs (oGLDs) from 2.6 million individual patients.5 All variables that may affect treatment assignment or outcomes were taken into account in the development of country-specific propensity scores.5 Based on these scores, initiation episodes of SGLT2 inhibitors and oGLDs were matched in a 1:1 ratio.5
After propensity matching, 470,128 patients were identified and included in the analysis (235,064 patients in each treatment group).5 Baseline characteristics were well-balanced between groups, with ≤3% standard differences for all variables.5 The patients had a mean age of 57 years, and around two-thirds of them had no established CV disease at baseline.5
Dr. Kosiborod noted that different SGLT2 inhibitors were prescribed across the countries, reflecting different regulatory approvals and practice patterns.5-7 In descending order, 70% of patients received dapagliflozin, 14% received empagliflozin, 9% received ipragliflozin (only in South Korea and Japan), 4% received canagliflozin, 3% received tofogliflozin (only in Japan), and 1% received luseogliflozin (only in Japan).6,7
Consistent benefits with SGLT2 inhibitors across a broad range of patient characteristics
As shown in Table 1, better outcomes were found in those who were initiated with SGLT2 inhibitors during the 1-year follow-up (374 and 394 days for the SGLT2 inhibitors and oGLDs groups, respectively).5 Except for all-cause death (ACD), data from Australia was not available for hospitalization for heart failure (hHF), myocardial infarction (MI), and stroke.5
The findings were also directionally consistent across countries.5 “What we observed for [lower risk of] heart failure and death were very consistent with the CVD-REAL study, despite a very different patient population,” said Dr. Kosiborod.4 This also suggests that the CV benefits of SGLT2 inhibitors are indeed a class effect, considering different SGLT2 inhibitors used in different countries.5
Most importantly, the CV benefits with SGLT2 inhibitors appear to be consistent regardless of CV disease at baseline (Figure 2).5 “These findings suggest that the cardiovascular effects of SGLT-2 inhibitors may extend across patient ethnic and racial backgrounds, geographic regions, as well as the CV risk continuum,” said Dr. Kosiborod.9
In CVD-REAL 2, hemoglobin A1c (HbA1c) was not included as an outcome measure. “The reason for that is that we know from clinical trials… that HbA1c does not appear to be significantly modified,” Dr. Kosiborod explained.4 Although this does not discount the importance of lowering HbA1c in preventing microvascular outcomes, “but from a cardiologist’s standpoint, we really should think about this class as a class that lowers CV risk regardless of HbA1c,” he said.4
Findings to be confirmed in the ongoing DECLARE-TIMI 58 trial
Due to the observational nature of CVD-REAL 2 study, the possibility of residual, unmeasured confounding cannot be excluded.5 However, the investigators believed that the findings of CVD-REAL 2 may be confirmed by the ongoing DECLARE-TIMI 58 trial, which recruited a broad population of type 2 diabetes patients.5 “DECLARE-TIMI 58 is going to come at a critical juncture,” noted Dr. Kosiborod.7
In fact, the length of median follow-up in DECLARE-TIMI 58 is expected to be more than 4 years, which is longer than the EMPA-REG OUTCOME (3.1 years) and CANVAS Program (2.4 years).10 Besides the immediate effects of the SGLT2 inhibitors, the longer follow-up of patients might be able to further elucidate the long-term clinical impact due to the favorable effects on mediators of atherosclerotic CV disease risk.10
“The underlying hypothesis of the DECLARE-TIMI 58 trial is that the improvement of multiple metabolic and hemodynamic… might improve CV outcomes not only in populations with established CV disease, but also in populations with multiple CV risk factors,” the DECLARE-TIMI 58 investigators wrote.10
1. Kosiborod M, Cavender MA, Fu AZ, et al. Lower Risk of Heart Failure and Death in Patients Initiated on Sodium-Glucose Cotransporter-2 Inhibitors Versus Other Glucose-Lowering Drugs: The CVD-REAL Study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors). Circulation. 2017;136(3):249-259.
2. Rodriguez F. How Broad Are the Benefits of SGLT-2 Inhibitors? (Accessed March 27, 2018, at https://www.jwatch.org/na46326/2018/03/11/how-broad-are-benefits-sglt-2-inhibitors).
3. CVD-REAL 2: SGLT-2 Inhibitors Associated With Lower Cardiovascular Risk Versus Other Glucose-Lowering Drugs. ACC News Story. 2018 (Accessed March 27, 2018, at http://www.acc.org/latest-in-cardiology/articles/2018/03/07/15/08/sun-445pm-cvd-real-2-lower-risk-of-cv-events-and-death-associated-with-sglt-2-inhibitors-acc-2018).
4. SGLT-2 Inhibitors Tied to Less Death, HF, MI, Stroke: CVD REAL 2. Medscape. 2018 (Accessed March 27, 2018, at https://www.medscape.com/viewarticle/894230#vp_1).
5. Kosiborod M, Lam CSP, Kohsaka S, et al. Lower Cardiovascular Risk Associated with SGLT-2i in >400,000 Patients: The CVD-REAL 2 Study. J Am Coll Cardiol. 2018 [Epub ahead of print].
6. HF, Survival Gains From SGLT-2 Inhibitors Seen in Lower-Risk Patients: CVD REAL. Medscape. 2017 (Accessed March 27, 2018, at https://www.medscape.com/viewarticle/877647#vp_1).
7. CVD-REAL Results in More Diverse Countries Link SGLT2s to Lower Risk of Death, Heart Attack, Stroke. AJMC. 2018 (Accessed March 28, 2018, at http://www.ajmc.com/conferences/acc-2018/cvdreal-results-in-more-diverse-countries-link-sglt2s-to-lower-risk-of-death-heart-attack-stroke).
8. CVD-REAL. A multinational, retrospective, observational study in patients with type 2 diabetes mellitus who are initiating treatment with SGLT-2 inhibitor or another glucose-lowering drug. (Accessed March 26, 2018, at https://www.cvdreal.com/cvd-real-study.html).
9. SGLT-2 Inhibitors Linked to Lowered Risk of Mortality, MI, Stroke, and Hospitalization for Heart Failure. MD Magazine. 2018 (Accessed April 1, 2018, at http://www.mdmag.com/conference-coverage/acc-2018/sglt2-inhibitor-linked-to-lowered-risk-of-mortality-mi-stroke-and-hospitalization-for-heart-failure).
10. Raz I, Mosenzon O, Bonaca MP, et al. DECLARE-TIMI 58: Participants’ baseline characteristics. Diabetes Obes Metab. 2018 [Epub ahead of print].