In HF, T2D, CKD, or atherosclerotic CVD, SGLT-2 inhibitors reduce HF hospitalizations and CV mortality

A meta-analysis of sodium-glucose cotransporter-2 (SGLT-2) inhibitors found that they reduced risk of heart failure (HF) events and cardiovascular (CV) death in patients with heart failure (HF), type 2 diabetes (T2D), chronic kidney disease (CKD), or atherosclerotic cardiovascular disease (CVD). It included 15 randomized controlled trials with more than 100,000 patients, five each on dapagliflozin and empagliflozin, two each on canagliflozin and sotagliflozin, and one on ertugliflozin. A separate recent trial of patients with CVD but without diabetes found that semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, reduced CV events.

The meta-analysis (by Usman et al.) was published in the July issue of The Lancet Diabetes & Endocrinology. The study in nondiabetic patients (by Lingvay et al.) was published by Diabetes Care on June 22. The following commentary by Doreen Zhu, MD, and William G. Herrington, MD, discusses both studies and was published in the ACP Journal Club section of Annals of Internal Medicine on Nov. 5.

There is a growing appreciation of the global burden of CV-kidney-metabolic (CKM) syndrome, which is linked to excess CV morbidity and mortality. The pathophysiologic interactions among CVD, CKD, and metabolic risk factors (e.g., diabetes, obesity, dyslipidemia, and hypertension) are multidirectional and complex. However, large trials have identified treatment strategies that are simple to implement. The 2 new publications by Lingvay and colleagues and Usman and colleagues expand on studies that have shown important risk-modifying properties of SGLT-2 inhibitors and GLP-1 receptor agonists beyond their glucose-lowering effects.

The systematic review and meta-analysis by Usman and colleagues provide the latest summary of CV data from large placebo-controlled SGLT-2 inhibitor trials, which include results from >100 000 patients. Analyses showed clear benefits of SGLT-2 inhibitors on CV death and HF complications in patients with T2D, atherosclerotic CVD, HF, CKD, and combinations thereof. The data support clinical guidelines that consider SGLT-2 inhibitors as foundational therapies in patients with T2D at risk for CVD and in patients with CKD and HF (regardless of diabetes status).

Large placebo-controlled trials have shown that doses of GLP-1 receptor agonists aiming to improve glycemic control also reduce CV risk in patients with T2D. The SELECT trial tested the effect of the higher weight-loss dose of semaglutide (2.4 mg/wk subcutaneously) on risk for atherosclerotic CVD in persons with existing CVD and overweight or obesity but without diabetes. Subgroup analyses from SELECT reported by Lingvay and colleagues showed that the benefits of semaglutide for major adverse CV events and a HF composite were not modified by baseline HbA1c levels, with benefits apparent at normal levels of HbA1c. The suggestion of effect modification for all-cause mortality should not be overemphasized because the treatment–subgroup interaction (P=0.03) was uncorrected for multiplicity, and benefits for all-cause mortality are expected to vary with the proportion of deaths due to different CV and non-CV causes (which may differ by baseline HbA1c levels). The exploration of effects by change in HbA1c levels were based on postrandomization subgroups and are challenging to interpret. Nevertheless, taken together, these subgroup analyses are consistent with the concept that dysglycemia (and by extension improved glycemic control) is not a prerequisite for the CV benefits conferred by weight-loss doses of GLP-1 receptor agonists. Further large clinical outcome trials of these drugs should be done in other populations with overweight and obesity that might benefit.

We should not forget the “K” in CKM syndrome! The reported CV benefits of GLP-1 receptor agonists and SGLT-2 inhibitors in the SELECT subgroup analyses and Usman and colleagues' meta-analysis complement previously reported benefits for kidney outcomes with both drug classes. With increasing evidence of efficacy across broadening populations at risk, a key challenge is how to implement the treatments at scale in all patients who have been shown to benefit. We predict different and complementary mechanisms of CV benefits and kidney protection from SGLT-2 inhibitors and GLP-1 receptor agonists. So although effects of combined use have not been formally tested (e.g., in large 2 × 2 factorial trial designs), we predict additional cardiorenal protection by concomitant use in patients with indications for both drugs.