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)

Abstract

Background: Reduction in cardiovascular death and hospitalization for heart failure (HHF) was recently reported with the sodium-glucose cotransporter-2 inhibitor (SGLT-2i) empagliflozin in patients with type 2 diabetes mellitus who have atherosclerotic cardiovascular disease. We compared HHF and death in patients newly initiated on any SGLT-2i versus other glucose-lowering drugs in 6 countries to determine if these benefits are seen in real-world practice and across SGLT-2i class.

Methods: Data were collected via medical claims, primary care/hospital records, and national registries from the United States, Norway, Denmark, Sweden, Germany, and the United Kingdom. Propensity score for SGLT-2i initiation was used to match treatment groups. Hazard ratios for HHF, death, and their combination were estimated by country and pooled to determine weighted effect size. Death data were not available for Germany.

Results: After propensity matching, there were 309 056 patients newly initiated on either SGLT-2i or other glucose-lowering drugs (154 528 patients in each treatment group). Canagliflozin, dapagliflozin, and empagliflozin accounted for 53%, 42%, and 5% of the total exposure time in the SGLT-2i class, respectively. Baseline characteristics were balanced between the 2 groups. There were 961 HHF cases during 190 164 person-years follow-up (incidence rate, 0.51/100 person-years). Of 215 622 patients in the United States, Norway, Denmark, Sweden, and the United Kingdom, death occurred in 1334 (incidence rate, 0.87/100 person-years), and HHF or death in 1983 (incidence rate, 1.38/100 person-years). Use of SGLT-2i, versus other glucose-lowering drugs, was associated with lower rates of HHF (hazard ratio, 0.61; 95% confidence interval, 0.51-0.73; P<0.001); death (hazard ratio, 0.49; 95% confidence interval, 0.41-0.57; P<0.001); and HHF or death (hazard ratio, 0.54; 95% confidence interval, 0.48-0.60; P<0.001) with no significant heterogeneity by country.

Conclusions: In this large multinational study, treatment with SGLT-2i versus other glucose-lowering drugs was associated with a lower risk of HHF and death, suggesting that the benefits seen with empagliflozin in a randomized trial may be a class effect applicable to a broad population of patients with type 2 diabetes mellitus in real-world practice.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02993614.

Keywords: canagliflozin; dapagliflozin; death; diabetes mellitus; empagliflozin; heart failure; sodium glucose transporter 2.

Figure 1.

Patient flow chart for all countries/databases combined. A large number of patients were excluded from the other GLD group because of the protocol mandated 1:1 match, and given the smaller number of patients in the SGLT-2i group. GLD indicates glucose-lowering drug; and SGLT-2i, sodium-glucose cotransporter-2 inhibitor.

Figure 2.

Contribution of the SGLT-2 inhibitor class as a proportion of exposure time in the propensity-match cohorts. A, All countries combined. B, United States only. C, European countries combined. HHF indicates hospitalization for heart failure; and SGLT-2, sodium-glucose cotransporter-2.

Figure 3.

Hazard ratios and 95% CI for the outcome of HHF. A, On treatment, unadjusted. B, On treatment, adjusted (model adjusted for history of heart failure, age, sex, frailty, history of myocardial infarction, history of atrial fibrillation, hypertension, obesity/body mass index, duration of diabetes mellitus, ACE inhibitor or ARB use, β-blocker or α-blocker use, Ca2⁺ channel blocker use, loop diuretic use, thiazide diuretic use). C, Intent-to-treat, unadjusted. ACE indicates angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; CI, confidence interval; CPRD, Clinical Practice Research Datalink; DPV, Diabetes Patientenverlaufsdokumentation (Diabetes Prospective Follow-Up); HHF, hospitalization for heart failure; oGLD, other glucose-lowering drugs; SGLT-2i, sodium-glucose cotransporter-2 inhibitor; and THIN, The Health Improvement Network.

Figure 4.

Hazard ratios and 95% CI for the outcome of all-cause death and composite of hospitalization for heart failure or all-cause death. A, All-cause death: on treatment, unadjusted. B, All-cause death: on treatment, adjusted (model adjusted for history of heart failure, age, sex, frailty, history of myocardial infarction, history of atrial fibrillation, hypertension, obesity/body mass index, duration of diabetes mellitus, ACE inhibitor or ARB use, β-blocker or α-blocker use, Ca2⁺ channel blocker use, loop diuretic use, thiazide diuretic use). C, All-cause death: intent-to-treat, unadjusted. D, Hospitalization for heart failure or all-cause death: on treatment, unadjusted. E, Hospitalization for heart failure or all-cause death: on treatment, adjusted (model adjusted for history of heart failure, age, sex, frailty, history of myocardial infarction, history of atrial fibrillation, hypertension, obesity/body mass index, duration of diabetes mellitus, ACE inhibitor or ARB use, β-blocker or α-blocker use, Ca2⁺ channel blocker use, loop diuretic use, thiazide diuretic use). F, Hospitalization for heart failure or all-cause death: intent-to-treat, unadjusted. ACE indicates angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; CI, confidence interval; CPRD, Clinical Practice Research Datalink; DPV, Diabetes Patientenverlaufsdokumentation (Diabetes Prospective Follow-Up); oGLD, other glucose-lowering drugs; SGLT-2i, sodium-glucose cotransporter-2 inhibitor; and THIN, The Health Improvement Network.