SGLT2 inhibition: Major and early impact on heart failure hospitalisation risk

The number and relative timing of events prevented with SGLT2 inhibitors vary across the cardiovascular-kidney-metabolic spectrum. Still, opportunities to modify this risk emerge early, particularly affecting heart failure (HF) and major adverse cardiovascular events (MACE) outcomes, according to insights gathered from 4 large, placebo-controlled outcome trials of SGLT2 inhibitors.

These insights were presented by Dr Muthiah Vaduganathan (Brigham and Women's Hospital, MA, USA), who stated that SGLT2 inhibitors have offered salutary benefits in several disease states, including diabetes, chronic kidney disease (CKD), and HF [1]. The totality of evidence shows clinically relevant reductions in important endpoints such as MACE, HF hospitalisation, cardiovascular (CV) death, and measures of CKD progression. These estimates are often presented as hazard ratios, estimating relative treatment benefits. “We have little understanding of the relative timing of benefits across various endpoints,” said Dr Vaduganathan.

Thus, his team leveraged 4 large-scale trials sampling distinct populations, including patients with type 2 diabetes, CKD, and HF, to understand the absolute number and relative timing of CV and kidney events prevented with SGLT2 inhibitors. These trials were the CREDENCE trial of canagliflozin in patients with CKD (n=4,401); the CANVAS Program of canagliflozin evaluating CV outcomes in patients with type 2 diabetes (n=10,142); and the DAPA-HF (n=4,744) and DELIVER (n=6,263) trials of dapagliflozin in patients with HF across the left ventricular ejection fraction spectrum [2–5]. Uniquely, the results of this analysis expressed absolute risk reductions, over time, of distinct events.

The results showed that SGLT2 inhibitors have an early and substantial positive effect on the risk of HF hospitalisation. This benefit accrued in all at-risk populations, including those with or without HF at baseline. Early treatment effects on composite endpoints observed in trials were driven by non-fatal components, especially in the early period.

As the Figure shows, the number and timing of events prevented with SGLT2 inhibitors varied considerably across the studied populations. HF hospitalisations appeared to be the earliest event prevented. At 12 months, the authors estimated that 275 and 335 HF hospitalisations would be averted per 10,000 treated patients, based on DAPA-HF and DELIVER, respectively. Comparatively fewer HF hospitalisations were prevented by 12 months in CANVAS Program and CREDENCE, but these benefits increased over time, as did benefits in MACE. Early benefit for CV death was clearest in HF participants with reduced ejection fraction. For CKD progression, the largest projected number of events prevented was seen in CREDENCE. The effect of SGLT2 inhibitors on preventing end-stage kidney disease required years of treatment in patients at high risk. Earlier treatment may avert upfront risks of CV complications.

Figure: Timing of CV and kidney outcomes prevented per 10,000 patients treated with SGLT2 inhibitors [1]



CKD, chronic kidney disease; CV, cardiovascular; HF, heart failure; MACE, major adverse cardiovascular events.

1. 
   
   1. Vaduganathan M, et al. Timing of Cardio-Kidney Protection with SGLT2 Inhibitors: Insights from Four Large-scale Placebo-Controlled Outcome Trials. Late breaking clinical trials I, Heart Failure 2024, 11–14 May, Lisbon, Portugal.
   2. Perkovic V, et al. N Engl J Med 2019;380:2295–306.
   3. Neal B, et al. N Engl J Med 2017;377:644–57.
   4. McMurray JJV, et al. N Engl J Med 2019;381:1995–2008.
   5. Solomon SD, et al. N Engl J Med 2022;387:1089–98.

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Posted on 16 July 202416 July 2024