Abstract
Aims: The EMPA-REG OUTCOME trial demonstrated that the sodium-glucose cotransporter-2 inhibitor (SGLT2) empagliflozin reduces the risk of cardiovascular (CV) and kidney outcomes in patients with type 2 diabetes. We previously developed the parameter response efficacy (PRE) score, which translates drug effects on multiple short-term risk markers into a predicted long-term treatment effect on clinical outcomes. The main objective of this study was to assess the accuracy of the PRE score in predicting the efficacy of empagliflozin in reducing the risk of CV and kidney outcomes. Methods: Short-term (baseline to 6-months) changes in glycated hemoglobin (HbA1c), systolic blood pressure (SBP), urinary-albumin-creatinine-ratio (UACR), hemoglobin, body weight, high-density-lipoprotein (HDL) cholesterol, low-density-lipoprotein (LDL) cholesterol, uric acid, and potassium were determined among 7020 patients with type 2 diabetes and established CV disease in the EMPA-REG OUTCOME trial. The beta-coefficients, derived from a Cox proportional hazards model in a pooled database consisting of 6355 patients with type 2 diabetes, were applied to the short-term risk markers in the EMPA-REG OUTCOME trial to predict the empagliflozin-induced impact on CV (defined as a composite of non-fatal myocardial infarction, non-fatal stroke, or CV death) and kidney (defined as a composite of doubling of serum creatinine or end-stage kidney disease) outcomes. Results: Empagliflozin compared to placebo reduced HbA1c (0.6%), SBP (4.2 mmHg), UACR (13.0%), body weight (2.1 kg), uric acid (20.4 μmol/L), and increased hemoglobin (6.6 g/L), LDL-cholesterol (0.1 mmol/L) and HDL-cholesterol (0.04 mmol/L) (all p<0.01). Integrating these effects in the PRE score resulted in a predicted relative risk reduction (RRR) for the CV outcome of 6.4% (95% CI 1.4–11.7), which was less than the observed 14.7% (95% CI 1.3–26.4%) RRR. For the kidney outcome, the PRE score predicted a RRR of 33.4% (95% CI 26.2–39.8); the observed RRR was 46.9% (95% CI 26.8–61.5). In a subgroup of 2,811 patients with UACR ≥30 mg/g at baseline, the PRE score predicted RRR was 40.8% (95% CI 31.2–49.1) vs. the observed RRR of 40.8% (95% CI 12.4–60.0) for the kidney outcome. Conclusions: Integrating multiple short-term risk marker changes in the PRE score underestimated the effect of empagliflozin on CV and kidney outcomes, suggesting that the currently used risk markers do not fully capture the effect of empagliflozin. In patients with increased albuminuria, the PRE score adequately predicted the effect of empagliflozin on kidney outcomes.
Highlights
Major cardiovascular (CV) outcomes trials of sodium-glucose cotransporter-2 (SGLT2) inhibitors, developed as antihyperglycemic drugs for the treatment of type 2 diabetes, have consistently demonstrated that these drugs reduce the relative risks of CV outcomes and slow the progression of kidney function decline in patients with type 2 diabetes at high CV risk (McGuire et al, 2021)
The EMPA-REG OUTCOME trial was the first published trial to demonstrate the benefit of an SGLT2 inhibitor, empagliflozin, for CV and kidney protection (Barnett et al, 2014; Zinman et al, 2015)
The relationships between risk markers and CV, or kidney outcomes were established at baseline in a background population derived from the ALTITUDE, RENAAL and IDNT trials, clinical trials conducted in patients with type 2 diabetes at high risk of kidney events or with established CV disease (Supplementary Table S1)
Summary
Major cardiovascular (CV) outcomes trials of sodium-glucose cotransporter-2 (SGLT2) inhibitors, developed as antihyperglycemic drugs for the treatment of type 2 diabetes, have consistently demonstrated that these drugs reduce the relative risks of CV outcomes and slow the progression of kidney function decline in patients with type 2 diabetes at high CV risk (McGuire et al, 2021). The efficacy of SGLT2 inhibitors in preventing CV outcomes and delaying diabetic kidney disease progression is unlikely explained by improvement in glycemic control alone. Head-tohead comparison of the SGLT2 inhibitor canagliflozin with the sulfonylurea derivative glimepiride showed that at equal glycemic control, canagliflozin reduced the rate of kidney function decline (Heerspink et al, 2017). The SGLT2 inhibitor dapagliflozin did not reduce glycated hemoglobin (HbA1c) but significantly reduced the risk of CV events and kidney failure (Persson et al, 2021). Numerous studies have shown that SGLT2 inhibitors exert additional effects beyond their effects on HbA1c. These effects can contribute to long-term CV and kidney protection (van Bommel et al, 2017; Vallon and Verma, 2021). Experimental and clinical studies have shown anti-inflammatory and anti-fibrotic effects, reflected by reductions in interleukin-6 and monocyte chemoattractant protein-1, such effects may be secondary to improvement in glycemic control (Vallon et al, 2014; Tahara et al, 2017; Mancini et al, 2018)
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