JFP Declare Diabetes vol68

Study Design, Population, and Key Outcomes of DECLARE-TIMI 58 Compared With Other Cardiovascular Outcomes Trials for Sodium-Glucose Cotransporter-2 Inhibitors

Dapagliflozin is a selective and reversible sodium-glucose cotransporter-2 inhibitor (SGLT-2i) that improves glycemic control in patients with type 2 diabetes (T2D). In cardiovascular (CV) outcomes trials of 2 other drugs in the SGLT-2i class, empagliflozin and canagliflozin reduced the risk of major adverse CV events (MACE) in patients with T2D and established CV disease or high CV risk. The DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events) study assessed the CV safety and efficacy of dapagliflozin in patients with T2D, including patients with CV disease risk factors and those with established CV disease. In the primary safety analysis of DECLARE-TIMI 58, dapagliflozin showed noninferiority for 3-point MACE (CV death, myocardial infarction, or ischemic stroke) compared with placebo. In the primary efficacy analysis, dapagliflozin was associated with a significant reduction in the risk of CV death or hospitalization for heart failure, although the risk reduction for 3-point MACE was not statistically significant. This newsletter reviews the DECLARE-TIMI 58 study design, patient baseline characteristics, and key study outcomes and compares them with those of the 2 previous SGLT-2i CV outcomes trials. It also discusses the potential effect of differences in study design and population on the applicability of the DECLARE-TIMI 58 study results to real-world clinical practice.

Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) are a relatively new class of oral glucose-lowering drugs that improve glycemic control in patients with type 2 diabetes (T2D) by decreasing renal glucose reabsorption and increasing urinary glucose excretion.¹ In addition, SGLT-2is potentially reduce cardiovascular (CV) risk through several pathways, including reductions in body weight, blood pressure (BP), uric acid, and albuminuria; decreases in plasma volume and arterial stiffness (preload and afterload); and improvements in insulin sensitivity.^2,3

Dapagliflozin is a selective and reversible SGLT-2i that reduces glycated hemoglobin (A1C), fasting and postprandial plasma glucose levels, body weight, and BP in patients with T2D, both as monotherapy and add-on treatment to other glucose-lowering therapy.^4,5 In addition to glycemic effects, dapagliflozin may have a potential benefit for reducing CV risk. A meta-analysis of dapagliflozin clinical studies found reductions in the risks of hospitalization for heart failure (HF) and myocardial infarction (MI) with dapagliflozin treatment.⁶ A large-scale prospective CV outcomes trial (CVOT) determined the effects of dapagliflozin on the risk of CV events.

Previously, 2 SGLT-2is have been shown to reduce the risk of major adverse CV events (MACE) in patients with T2D and established CV disease or high CV risk in CVOTs: empagliflozin (EMPA-REG OUTCOME [Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients]) and canagliflozin (CANVAS [Canagliflozin Cardiovascular Assessment Study]).^7,8 These studies also showed reductions in the risk of CV death with empagliflozin⁷ and the risk of hospitalization for HF with both empagliflozin and canagliflozin.^7,8

The results of these CVOTs apply primarily to the prevention of recurrent CV events rather than the prevention of new CV events because EMPA-REG OUTCOME enrolled only patients with established CV disease (CVD),⁹ and in CANVAS, the reduction in the risk of CV events was considerably smaller for patients without prior CV events than in the overall population or those with prior CV events.^8,10

DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events; ClinicalTrials.gov identifier: NCT01730534) was a multinational study designed to assess the effects of dapagliflozin on the incidence of MACE in patients with T2D and included a majority of patients with multiple CVD risk factors, as well as those with established CVD.¹¹ The results of DECLARE-TIMI 58, reported in November 2018, indicate that dapagliflozin achieved its primary safety end point of noninferiority for 3-point MACE (CV death, MI, or ischemic stroke) and one of its primary efficacy end points of a significant reduction in the risk of CV death or hospitalization for HF, although the other primary efficacy end point (3-point MACE) did not show a statistically significant reduction in risk.¹²

This newsletter reviews the DECLARE-TIMI 58 study design, patient baseline characteristics, and key outcomes, comparing them with those of the 2 previous SGLT-2i CVOTs, and discusses the potential effect of differences in design and study population on applicability of the study results to real-world clinical practice.

DECLARE-TIMI 58 Study Design

DECLARE-TIMI 58 was a randomized, double-blind, placebo-controlled study of dapagliflozin.¹¹ The study randomized >17,000 patients with T2D (A1C ≥6.5% to <12.5%) who were ≥40 years of age with established CVD or age ≥55 years (men) or ≥60 years (women) and had ≥1 traditional CVD risk factor (Figures 1A and 2).¹¹

After a 4- to 8-week single-blind placebo run-in period, patients were randomized (1:1) to receive dapagliflozin
10 mg daily or matched placebo added on to background glucose-lowering therapy (Figure 1A).¹¹ The study duration was ~6 years (median follow-up of 4.2 years),¹² although the actual duration was event-driven, with ≥1390 patients with MACE required for the primary analysis.¹¹

The primary safety end point and one of the primary efficacy end points was the composite outcome of CV death, MI, or ischemic stroke (3-point MACE) with dapagliflozin versus placebo (Figure 1A), which was assessed by noninferiority analysis (upper bound of the 95% confidence interval [CI] of the hazard ratio [HR] for dapagliflozin versus placebo <1.3 with a 1-sided alpha level of 0.023).^11,12

The primary efficacy end points were the above-mentioned 3-point MACE and the composite outcome of CV death or hospitalization for HF with dapagliflozin versus placebo (Figure 1A).^11,12 Originally, hospitalization for HF was the key secondary end point; however, after the EMPA-REG OUTCOME study reported a reduction in the risk of HF hospitalization,⁷ the DECLARE-TIMI 58 study protocol was modified after completion of enrollment (but before any data monitoring committee efficacy assessments) to include the composite of CV death or hospitalization for HF as a second primary efficacy end point.¹¹

Figure 1. Study designs of the (A) DECLARE-TIMI 58,^11,12 (B) EMPA-REG OUTCOME,⁹ and (C) CANVAS^8,13,14 studies in patients with T2D

The DECLARE-TIMI 58 study also included 2 prespecified secondary efficacy end points: (1) the composite renal end point (confirmed, sustained ≥40% decline in estimated glomerular filtration rate [eGFR] to
<60 mL/min/1.73 m²; end-stage renal disease [dialysis ≥90 days; kidney transplant; or confirmed, sustained eGFR <15 mL/min/1.73 m²]; or renal or CV death) and (2) all-cause mortality.^11,12

Comparison With EMPA-REG OUTCOME and CANVAS Study Designs

While all 3 studies were randomized, double-blind, placebo-controlled trials, the designs of the DECLARE-TIMI 58, EMPA-REG OUTCOME, and CANVAS studies differed, particularly with respect to population size and composition, inclusion criteria, follow-up duration, and primary end points (Figure 1).

The EMPA-REG OUTCOME study randomized >7000 patients with T2D who were treatment naive (A1C ≥7% to ≤9%) or on background glucose-lowering therapy (A1C ≥7% to ≤10%) with established CVD (Figures 1B and 2).⁹ After a 2-week placebo run-in period, patients were randomized (1:1:1) to receive once-daily empagliflozin (10 or 25 mg) or matched placebo, in addition to background glucose-lowering therapy.^7,9

The CANVAS program included 2 studies (CANVAS and CANVAS-R) that enrolled a total of ~10,000 patients with T2D (A1C ≥7% to ≤10.5%) and high CVD risk (aged ≥30 years with established CVD or aged ≥50 years with ≥2 CVD risk factors [Figures 1C and 2]).^8,13,14 After a 2-week placebo run-in period, patients in the CANVAS study were randomized (1:1:1) to receive once-daily canagliflozin (100 or 300 mg) or matched placebo.^8,13 In the CANVAS-R study of renal outcomes, patients were randomized (1:1) to receive once-daily canagliflozin 100 mg (with an optional increase to 300 mg from week 13) or matched placebo.^8,14

The number of patients with established CVD in the DECLARE-TIMI 58 study was similar to that in the EMPA-REG OUTCOME and CANVAS studies; however, DECLARE-TIMI 58 also included >10,000 patients with multiple CVD risk factors without established CVD. To date, this is the largest population of patients without established CVD enrolled in a CVOT.¹⁵ This study population allowed for the assessment of the effectiveness of an SGLT-2i (dapagliflozin) in a large population of patients with T2D and a wide range of CVD risk.¹¹ The inclusion criteria for A1C were also broader in the DECLARE-TIMI 58 study than those in the EMPA-REG OUTCOME or CANVAS studies (Figure 2),^9,11,13 giving it the potential to include patients with a wider range of disease severity.

Figure 2. Summary of inclusion criteria for the DECLARE-TIMI 58,^11,15 EMPA-REG OUTCOME,⁹ and CANVAS^13,14 studies

Median follow-up in the DECLARE-TIMI 58 study was longer (4.2 years) than that in the EMPA-REG OUTCOME and CANVAS studies (3.1 and 2.4 years, respectively [Figure 1]).^7,8,12 The longer follow-up duration of DECLARE-TIMI 58 may have allowed for evaluation of the long-term effects of an SGLT-2i on potential mediators of CV risk, including BP, lipid parameters, and progression of kidney disease.¹⁵

The primary end point of the EMPA-REG OUTCOME and CANVAS studies was 3-point MACE (Figure 1).^9,13 In the DECLARE-TIMI 58 study, the primary safety end point was 3-point MACE (noninferiority compared with placebo); this study also included 2 primary efficacy end points: 3-point MACE and the composite of CV death or hospitalization for HF.¹¹ The inclusion of the HF hospitalization component of this prespecified end point may allow for confirmation of the reductions in HF events with an SGLT-2i that were observed in both the EMPA-REG OUTCOME and CANVAS studies.^7,8,16

The key secondary end point in EMPA-REG OUTCOME was the composite of the primary outcome plus hospitalization for unstable angina,⁹ while the secondary end point in CANVAS (measured in a subset of patients) was fasting measures of β-cell function, using the homeostasis model assessment and the proinsulin-to-insulin ratio.¹³ The primary end point of the CANVAS-R study was albuminuria progression, defined as a change from normoalbuminuria to micro- or macroalbuminuria, or from micro- to macroalbuminuria with a ≥30% increase in albumin-to-creatinine ratio.¹⁴ This outcome is similar to the prespecified secondary composite renal end point of the DECLARE-TIMI 58 study (described previously).¹¹

DECLARE-TIMI 58 Study Population

The DECLARE-TIMI 58 study randomized 17,190 patients; 30 patients at 1 study site were excluded from all analyses because of noncompliance with Good Clinical Practice at this site during a different trial.^11,15 Thus, a total of 17,160 patients, comprising 6974 patients (40.6%) with established CVD and 10,186 (59.4%) with multiple CVD risk factors, were included in the primary analysis.¹²

In the DECLARE-TIMI 58 study population, patients had a mean ± standard deviation (SD) age of 63.8 ± 6.8 years, body mass index (BMI) of 32.1 ± 6 kg/m², and A1C of 8.3% ± 1.2% (67 ± 13.1 mmol/mol) at baseline (Table 1).¹⁵ Most patients were male (62.6%) and white (79.6%). When patients with established CVD were compared with those with multiple risk factors, many baseline characteristics were similar, including mean ± SD age (62.5 ± 8.1 vs 64.7 ± 5.6 years), BMI (32.1 ± 6 vs 32 ± 6 kg/m²), and A1C (8.4% ± 0.9% vs 8.3% ± 0.9%
[68 ± 9.7 vs 67 ± 9.7 mmol/mol]), as well as duration of diabetes (12 vs 11.7 years).¹⁵ The proportion of male patients was higher in the established CVD subgroup than in the multiple risk factors subgroup (72.1% vs 56.1%, respectively). In both subgroups, the prevalence of CV risk factors was high, particularly for medically treated hypertension (87.7% and 90.6% in the established CVD and multiple risk factor subgroups, respectively).

The established CVD subgroup included smaller proportions of patients who used metformin (74.6% vs 81.2%) and sulfonylureas (38% vs 43.2%) than the multiple risk factor subgroup, while insulin use was more common (44.2% vs 36.4%).¹⁵ As expected, a higher proportion of patients in the established CVD subgroup used β-blockers (66.6% vs 32.3%), antiplatelet anticoagulant agents (aspirin [71.1% vs 39.1%], clopidogrel [24.7% vs 1.5%], warfarin [6.1% vs 3.5%], direct oral anticoagulants [2.1% vs 1.1%]), and statins (82.2% vs 63.7%) than in the multiple risk factor subgroup.¹⁵

TABLE 1. Summary of key baseline characteristics across the DECLARE-TIMI 58, EMPA-REG OUTCOME, and CANVAS studies

Comparison With EMPA-REG OUTCOME and CANVAS Study Populations

The number of randomized patients in the DECLARE-TIMI 58 study (N=17,160)¹² was larger than that in the EMPA-REG OUTCOME (N=7028)⁷ or CANVAS (N=10,142)⁸ studies.

Patient baseline characteristics, such as age, A1C, BMI, duration of T2D or time since T2D diagnosis, and medication use, were generally similar across the DECLARE-TIMI 58, EMPA-REG OUTCOME, and CANVAS study populations (Table 1).^7-9,12,15 Patients in DECLARE-TIMI 58 had higher baseline eGFR (ie, less severe renal impairment) than those in the previous CVOTs (Table 1); however, because of the larger study population, longer follow-up duration, and prespecified renal end points of DECLARE-TIMI 58, the study still provides insights into renal outcomes with dapagliflozin.¹⁵

The key difference between the DECLARE-TIMI 58 study and previous CVOTs is that it included a smaller proportion of patients with established CVD (~40% of patients),¹² whereas ~99% of patients in EMPA-REG OUTCOME⁹ and ~66% in CANVAS⁸ had established CVD (Table 2). In DECLARE-TIMI 58, ~60% of enrolled patients had multiple risk factors without established CVD,¹² which provided a population who were at an earlier stage of the CVD risk continuum (Table 2).

TABLE 2. CVD and other medical history at baseline in the DECLARE-TIMI 58, EMPA-REG OUTCOME, and CANVAS studies

The nature of the DECLARE-TIMI 58 study population may increase the generalizability of the study results to patients with T2D seen in real-world clinical practice.^15,17 In a retrospective study using data from the US National Health and Nutrition Examination Survey, ~75% of patients with T2D surveyed did not have CVD, while ~67% had hypertension or hypercholesterolemia.¹⁷ This indicates that the study population of DECLARE-TIMI 58 may be more generalizable to the T2D population in the United States than populations from previous CVOTs of SGLT-2is.

DECLARE-TIMI 58 Key Outcomes

Dapagliflozin showed noninferiority compared with placebo with regard to the 3-point MACE primary safety end point (HR, 0.93 [95% CI, 0.84–1.03]; P<.001 for noninferiority).¹² In the efficacy analysis, the risk of CV death or hospitalization for HF was significantly reduced by 17% with dapagliflozin vs with placebo (HR, 0.83 [95% CI, 0.73–0.95]; P=.005), although the risk of 3-point MACE was not significantly different (P=.17 for superiority). Of note, the reduced risk of CV death or hospitalization for HF was driven by a lower rate of hospitalization for HF with dapagliflozin vs with placebo (2.5% vs 3.3%; HR, 0.73 [95% CI, 0.61–0.88]). Further, the risk reduction for CV death or hospitalization for HF was similar in patients with established CVD (HR, 0.83 [95% CI, 0.71–0.98]) and those with multiple risk factors (HR, 0.84 [95% CI, 0.67–1.04]).¹²

The rate of the composite renal end point (≥40% reduction in eGFR to <60 mL/min/1.73 m², end-stage renal disease, or death from renal or CV causes) was lower with dapagliflozin than with placebo (4.3% vs 5.6%; HR, 0.76 [95% CI, 0.67–0.87]), and the rate of death from any cause was numerically lower with dapagliflozin than with placebo (15.1 vs 16.4 per 1000 patient-years), although the overall all-cause mortality risk was similar between groups (HR, 0.93 [95% CI, 0.82–1.04]).¹² However, because the risk of 3-point MACE was not significantly reduced with dapagliflozin, these secondary end points were considered exploratory because of hierarchical statistical analyses.¹²

Comparison With EMPA-REG OUTCOME and CANVAS Results

The reduction in the risk of hospitalization for HF in DECLARE-TIMI 58¹² was similar to that observed in EMPA-REG OUTCOME (HR, 0.65 [95% CI, 0.50–0.85])⁷ and CANVAS (HR, 0.67 [95% CI, 0.52–0.87]).⁸ In contrast with DECLARE-TIMI 58, the risk of the primary 3-point MACE end point in EMPA-REG OUTCOME and CANVAS was significantly reduced with empagliflozin (HR, 0.86 [95% CI, 0.74–0.99]; P=.04)⁷ and canagliflozin
(HR, 0.86 [95% CI, 0.75–0.97]; P=.02)⁸ than with placebo.

Improvements in renal outcomes with dapagliflozin in DECLARE-TIMI 58 were similar to those observed in the 2 previous SGLT-2i CVOTs. CANVAS showed a reduction in the risk of the exploratory composite renal end point (40% reduction in eGFR, requirement for renal replacement therapy, or death from renal causes) with canagliflozin (HR, 0.60 [95% CI, 0.47–0.77]),⁸ and a secondary analysis of EMPA-REG OUTCOME reported a significant reduction in the risk of incident or worsening nephropathy (defined as progression to macroalbuminuria, doubling of serum creatinine with eGFR ≤45 mL/min/1.73 m², requirement for renal replacement therapy, or death from renal disease) with empagliflozin (HR, 0.61 [95% CI, 0.53–0.70]; P<.001).¹⁸

Key findings from a meta-analysis of the 3 CVOTs were that the results from these trials were generally consistent.¹⁹ SGLT-2is reduced MACE only in patients with established CVD but not in those without. Robust reductions in hospitalization for heart failure and on progression of renal disease were observed in patients with and without CVD. However, there were some differences in the results from these studies. The effect of empagliflozin on cardiovascular death was higher than that seen with canagliflozin or dapagliflozin, and the risk of amputations and fractures was only seen with canagliflozin. Furthermore, in a real-world study in a DECLARE-like population, outcomes results were similar to results from DECLARE-TIMI 58 for dapagliflozin; CV mortality and all-cause mortality were higher in the DECLARE-like study, which were attributed to a more frail population.²⁰

Conclusions

The DECLARE-TIMI 58 study assessed the CV safety and efficacy of dapagliflozin in a patient population that was larger and had a broader range of baseline CVD risk compared with previous CVOTs of SGLT-2is. Treatment with dapagliflozin significantly lowered the rate of CV death or hospitalization for HF compared with placebo, but the reduction in the risk of 3-point MACE did not reach statistical significance, most likely due to variations in study design and population characteristics. Despite the differences observed between DECLARE-TIMI 58 and previous studies in the risk of 3-point MACE, the recently reported results of DECLARE-TIMI 58 may be more generalizable to patients with T2D in clinical practice with a broad spectrum of CVD risk. Furthermore, the significant risk reduction for the primary efficacy end point of CV death or hospitalization for HF with dapagliflozin provides additional evidence of the potential benefits of SGLT-2is with regard to HF outcomes.

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