Clinical Pearls & Morning Reports

Posted by Carla Rothaus

Published May 25, 2022


What was unexpectedly learned from the EMPA-REG OUTCOME trial? 

Between 2012 and 2017, the Food and Drug Administration (FDA) and the European Medicines Agency approved canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin (all sodium–glucose cotransporter inhibitors) for reducing hyperglycemia in patients with type 2 diabetes. Read the NEJM Review Article here.

Clinical Pearls

Q: What role does sodium–glucose cotransporter 2 play in the kidney?

A: The reabsorption of glucose from the glomerular filtrate is an active process, which is linked to sodium and requires a carrier protein, referred to as a sodium–glucose cotransporter (SGLT). Two isoforms of SGLT have been described: SGLT1, which is located primarily in the small intestine, with little effect in the renal tubule; and SGLT2. SGLT2 is found almost exclusively in the epithelial cells of the proximal renal tubule, where it is responsible for more than 90% of glucose reabsorption and 65% of sodium reabsorption.

Q: What is the genesis of the many clinical trials evaluating cardiovascular outcomes with use of medications to treat diabetes?

A: In 2008, before the approval of the SGLT2 inhibitors, concern about the cardiovascular safety of rosiglitazone, a popular antidiabetic agent, led the FDA to issue a Guidance for Industry recommending that sponsors of new or recently approved antidiabetic agents “demonstrate that the therapy will not result in an unacceptable increase in cardiovascular risk.” To satisfy this requirement, a number of large clinical outcome trials were conducted to evaluate such agents, including SGLT2 inhibitors, which had important actions on the heart and kidneys.

Morning Report Questions

Q: What was unexpectedly learned from the EMPA-REG OUTCOME trial?

A: The first completed large clinical outcome trial of an SGLT2 inhibitor in patients with type 2 diabetes, the EMPA-REG OUTCOME trial, compared empagliflozin with placebo in 7020 patients with cardiovascular disease. The primary end point was major adverse cardiac events (i.e., death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke). Not only was empagliflozin shown to be safe, but it also appeared to be cardioprotective. The risks of prespecified secondary end points were all reduced significantly as well, including cardiovascular death (by 38%); also reduced significantly were the risk of hospitalization for heart failure (by 35%) and all-cause death (by 32%). These reductions were observed across a broad spectrum of heart-failure risks, with significant beneficial effects observed as early as 2 to 3 weeks after the start of therapy. These favorable results were quite surprising to both the endocrine and cardiology communities, but the prevention of hospitalization for heart failure was soon and repeatedly confirmed.

Q: Are the cardiovascular benefits of SGLT2 inhibitors linked to their glucose-lowering properties?

A: The Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial was limited to patients who had heart failure with ejection fractions below 40%; 55% of the 4744 patients enrolled did not have type 2 diabetes. The patients randomly assigned to dapagliflozin had significant reductions in cardiovascular death or hospitalization for heart failure (the primary end point) (hazard ratio, 0.74; 95% CI, 0.65 to 0.85) and a significant (31%) reduction in hospitalization for heart failure. All-cause mortality and outpatient worsening of heart failure were also reduced. The improvements were similar in patients with and in those without type 2 diabetes, indicating that the cardiovascular benefits of the SGLT2 inhibitor were independent of its glucose-lowering properties.

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