Effect of Dapagliflozin on Cardiovascular Outcomes According to Baseline Kidney Function and Albuminuria Status in Patients With Type 2 Diabetes

Abstract

IMPORTANCE Sodium-glucose cotransporter 2 inhibitors, such as dapagliflozin, promote renal glucose excretion and reduce cardiovascular (CV) deaths and hospitalizations for heart failure (HHF) among patients with type 2 diabetes. The relative CV efficacy and safety of dapagliflozin according to baseline kidney function and albuminuria status are unknown. OBJECTIVE To assess the CV efficacy and safety of dapagliflozin according to baseline estimated glomerular filtration rate (eGFR) and urinary albumin to creatinine ratio (UACR). DESIGN, SETTING, AND PARTICIPANTSThis secondary analysis of the randomized clinical trial Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 compared dapagliflozin vs placebo in 17 160 patients with type 2 diabetes and a baseline creatinine clearance of 60 mL/min or higher. Patients were categorized according to prespecified subgroups of baseline eGFR (<60 vs Ն60 mL/min/1.73 m 2 ), urinary albumin to creatinine ratio (UACR; <30 vs Ն30 mg/g), and of chronic kidney disease (CKD) markers using these subgroups (0, 1, or 2). The study was conducted from May 2013 to September 2018. INTERVENTIONS Dapagliflozin vs placebo. MAIN OUTCOMES AND MEASURESThe dual primary end points were major adverse cardiovascular events (myocardial infarction, stroke, and CV death) and the composite of CV death or HHF.RESULTS At baseline, 1265 patients (7.4%) had an eGFR below 60 mL/min/1.73 m 2 , and 5199 patients (30.9%) had albuminuria. Among patients having data for both eGFR and UACR, 10 958 patients (65.1%) had an eGFR equal to or higher than 60 mL/min/1.73 m 2 and an UACR below 30 mg/g (mean [SD] age, 63.7 [6.7] years; 40.1% women), 5336 patients (31.7%) had either an eGFR below 60 mL/min/1.73 m 2 or albuminuria (mean [SD] age, 64.1 [7.1] years; 32.6% women), and 548 patients (3.3%) had both (mean [SD] age, 66.8 [6.9] years; 30.5% women). In the placebo group, patients with more CKD markers had higher event rates at 4 years as assessed using the Kaplan-Meier approach for the composite of CV death or HHF (3.9% for 0 markers, 8.3% for 1 marker, and 17.4% for 2 markers) and major adverse cardiovascular events (7.5% for 0 markers, 11.6% for 1 marker, and 18.9% for 2 markers). Estimates for relative risk reductions for the composite of CV death or HHF and for major adverse cardiovascular events were generally consistent across subgroups (both P > .24 for interaction), although greater absolute risk reductions were observed with more markers of CKD. The absolute risk difference for the composite of CV death or HHF was greater for patients with more markers of CKD (0 markers, −0.5%; 1 marker, −1.0%; and 2 markers, −8.3%; P = .02 for interaction). The numbers of amputations, cases of diabetic ketoacidosis, fractures, and major hypoglycemic events were balanced or numerically lower with dapagliflozin compared with placebo for patients with an eGFR below 60 mL/min/1.73 m 2 and an UACR of 30 mg/g or higher.CONCLUSIONS AND RELEVANCE The effect of dapagliflozin on the relative risk for CV...

Nonalbuminuric Diabetic Kidney Disease and Risk of All-Cause Mortality and Cardiovascular and Kidney Outcomes in Type 2 Diabetes: Findings From the Hong Kong Diabetes Biobank

“…The secondary analysis of the Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction (DECLARE-TIMI) 58 randomized clinical trial found no heterogeneity in the effect on HHF across DKD markers (eGFR <60 mL/min/1.73 m 2 and albuminuria) and reported a larger effect in patients with albuminuria plus decreased eGFR. 33 The current study demonstrated that participants with decreased eGFR only had a higher risk of HHF than participants without DKD, and the finding remained unchanged after excluding participants with baseline eGFR <30 mL/min/1.73 m 2 . As the study combined patients with either reduced eGFR or albuminuria as one group, 33 it remains to be confirmed how much patients with reduced eGFR in the absence of albuminuria would benefit from this drug.…”

“…33 The current study demonstrated that participants with decreased eGFR only had a higher risk of HHF than participants without DKD, and the finding remained unchanged after excluding participants with baseline eGFR <30 mL/min/1.73 m 2 . As the study combined patients with either reduced eGFR or albuminuria as one group, 33 it remains to be confirmed how much patients with reduced eGFR in the absence of albuminuria would benefit from this drug.…”

Renal Histologic Findings in Necropsies of Type 2 Diabetes Mellitus Patients

“…In this regard, the DECLARE study in T2DM patients with or at risk of atherosclerotic cardiovascular disease found that treatment with dapagliflozin was associated with a 24% reduction in the renal endpoint (hazard ratio, 0.76; 95% CI, 0.67–0.87). These findings demonstrate the effect of an SGLT2i in earlier stages of renal disease since in this study, 65% of patients showed no expression of any renal markers (eGFR < 60 mL/min/1.73 m 2 , microalbuminuria or macroalbuminuria: 93% showed eGFR > 60 mL/min/1.73 m 2 and 69.1% showed no albuminuria) and 59.4% of patients had no previous cardiovascular disease [ 24 , 25 ]. Interestingly, the use of SGLT2i seems to prevent and reduce diabetic kidney disease progression compared to placebo in this large and diverse population study in T2DM patients with or without established atherosclerotic cardiovascular disease, most of whom had preserved renal function.…”

Endpunkte zu mikrovaskulären Folgekomplikationen: klinische Endpunkte, patientenberichtete Endpunkte und Surrogatendpunkte, Methodik von Surrogatvalidierungsstudien

“…Auch in den Langzeitstudien zu mikrovaskulären Endpunkten mit der Substanzklasse der SGLT-2 Inhibitoren (SGLT-2 = sodium glucose transporter) wurde die anhaltende prozentuale Abnahme der GFR als ein Endpunkt betrachtet [58,59,60,61,62,63,64,65,66,67,68,69,70,71]. Eine Verdopplung des Serum-Kreatinins ist ein besonders starker Prädiktor für eine Nierenerkrankung im Endstadium.…”