SGLT2 Inhibitors: Is This the Start of a New Era?

Gregory A. Nichols, PhD


December 07, 2018

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a relatively new class of antihyperglycemic agents that lower blood glucose by enhancing urinary excretion of glucose.[1] This mechanism of action, along with the relatively modest HbA1c reduction when used as a second-line agent, left some clinicians underwhelmed.

Beginning in 2015, however, cardiovascular outcomes trials designed to demonstrate safety began reporting cardiovascular benefits—especially in heart failure—as well as reductions in albuminuria and increases in estimated glomerular filtration rate (eGFR).[2]

The American Heart Association (AHA) 2018 Scientific Sessions included reviews of existing data and exciting new clinical trial results on the benefits of SGLT2 inhibitors.

The Metabolic Face of Heart Failure

The Sunday afternoon symposium, "The Metabolic Face of Heart Failure," was presented by experts who reviewed what is currently known about SGLT2 inhibitors as well as the other newer classes of antihypeglycemics—dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists.

Dr Eugene Braunwald led with an overview of the positive effects of SGLT2 inhibitors on diabetes, heart failure, and renal dysfunction. The EMPA-REG OUTCOME trial was the first to report cardiovascular benefits, achieving a 14% risk reduction in the primary composite outcome with empagliflozin.[3] The result was driven by a 38% reduction in death from cardiovascular causes, with no significant differences in nonfatal myocardial infarction or stroke. The other key finding was a 35% reduction in risk for hospitalization for heart failure.

A subsequent pooled analysis of phase 3 trials of empagliflozin demonstrated a significant reduction in urine albumin-to-creatinine ratio (UACR).[4] Two years later, the CANVAS Program reported a 14% reduction in the same primary outcome with canagliflozin, along with a 33% reduction in hospitalization for heart failure and a 27% lower risk for progression of albuminuria. Risk for the composite outcome of a 40% reduction in eGFR, renal replacement therapy, or death from renal causes was reduced by 40%.[5]

A later report from CANVAS suggested a slowing of eGFR decline among those who were randomly assigned to canagliflozin.[6] Both EMPA-REG and CANVAS were conducted among patients with diabetes who had established atherosclerotic disease or were otherwise at high risk for cardiovascular disease.

Dr Subodh Verma further reviewed cardiovascular outcomes trials of SGLT2 inhibitors, as well as those for DPP-4 inhibitors and GLP-1 receptor agonists. Overall, DPP-4 inhibitors did not provide a cardiovascular benefit and produced mixed results on heart failure.

GLP-1 receptor agonists may provide some cardiovascular benefit, although Verma pointed out that the benefit may be limited to analogues of human GLP-1 rather than exendin-based or DPP-4–resistant analogues. He also noted that the reduction in major cardiovascular events with SGLT2 inhibitors was limited to patients with diabetes who had established cardiovascular disease.

Indeed, the DECLARE-TIMI 58 cardiovascular outcomes trial of dapagliflozin, which included patients who were at risk but did not have established cardiovascular disease, reported no benefit (or harm) in the risk for major cardiovascular events.[7] However, like EMPA-REG and CANVAS, DECLARE-TIMI 58 demonstrated a significant reduction in risk for hospitalization for heart failure (27%) and risk for the renal composite (24%). A meta-analysis of these three trials was published simultaneously with the 2018 AHA Scientific Sessions.[2]

EMPA-HEART Explains the Benefits

Although blood-pressure lowering and weight loss were seen in the treatment arms of the three SGLT2 inhibitor outcomes trials, they were not enough to account for the results. Thus, the mechanism by which these studies achieved their heart failure and mortality benefits has not been clear.

In a late-breaking clinical trials session, the EMPA-HEART study[8] was presented to a packed house. The goal of the randomized controlled trial was to examine the effects of empagliflozin (n = 49) versus placebo (n = 48) on left ventricular remodeling over 6 months among patients with type 2 diabetes, with or without prior heart failure. All participants had established cardiovascular disease (ie, prior coronary revascularization or history of myocardial infarction), normal kidney function (eGFR ≥ 60 mL/min/1.73 m2), and left ventricular (LV) ejection fraction (EF) of at least 30%. Most of the participants were men (93%).

The primary outcome was change in LV mass index from baseline. After statistical adjustment, the empagliflozin group attained a 2.6 g/m2 reduction in LV mass index versus -0.01 g/m2 with placebo (P = .01), with the greatest improvement occurring among those with baseline LV mass index > 60 g/m2.

In addition, the treatment group had a change in systolic blood pressure of -7.9 mm Hg versus -0.7 mm Hg (P = .003), an increase in hematocrit (2.4% vs 0.4%, P = .006), and an improvement in LVEF, though not significant (2.2% vs -0.01%, P = .07).

It is remarkable that these effects were observed over a follow-up of only 6 months. On the other hand, the short follow-up begs the question of whether the effects could be sustained or whether they would continue to separate over longer periods.

In any case, the study provided the first mechanistic explanation for the favorable heart failure and cardiovascular death benefits seen in the EMPA-REG OUTCOME, CANVAS Program, and DECLARE-TIMI 58 cardiovascular outcomes trials.

Other important studies of SGLT2 inhibitors are underway. In particular, whether these agents can reduce heart failure hospitalizations and cardiovascular deaths in patients without diabetes with preserved or reduced ejection fraction will be reported in 2020. Another large trial studying the renal benefits of SGLT2 inhibitors in patients both with and without diabetes has also been announced. The era of SGLT2 inhibitors may indeed be upon us.


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