Braunwald: SGLT2 inhibitors have influenced CV care regardless of diabetes status
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Two paradigm shifts have established SGLT2 inhibitors as an important drug class to treat cardiac dysfunction and HF with reduced ejection fraction in patients with and without diabetes, according to a presentation.
The first discussion of SGLT2 inhibitors was in a paper published in Diabetes in 1999, in which a novel agent was introduced to lower blood glucose in patients with diabetes, Eugene Braunwald, MD, Distinguished Hersey Professor of Medicine at Harvard Medical School and founding chairman of the TIMI Study Group at Brigham and Women’s Hospital, said during his keynote speech at the virtual Heart in Diabetes Conference.
A systematic review and meta-analysis published in the Annals of Internal Medicine in 2013 found that SGLT2 inhibitors may improve short-term outcomes in patients with type 2 diabetes, although its long-term safety and effects were unclear, Braunwald, a member of the Cardiology Today Editorial Board, said.
CV outcome trials for diabetes drugs became mandatory after an analysis of pooled data published in The New England Journal of Medicine in 2007 showed that rosiglitazone, a widely used antidiabetic drug, when compared with control options which varied based on the study, led to a 43% increased risk for MI and a 64% increased risk for CV death.
Other papers around this time had similar findings, which led the FDA in 2008 to instruct sponsors of new antidiabetic therapies that they had to demonstrate that the therapy would not increase CV risk, Braunwald said.
‘First big surprise’
The “first big surprise in this field,” Braunwald said, was the publication of the EMPA-REG Outcome trial in 2015. As Healio previously reported, empagliflozin (Jardiance, Boehringer Ingelheim) significantly reduced the risk for CV death and all-cause mortality in adults with type 2 diabetes and an established history of CVD.
“This was totally unexpected,” Braunwald said. “I remember when this paper was published, a lot of people just shook their heads and said, ‘We can’t quite believe it.’ We’re trying to find out if it’s dangerous for the heart, and here we see a reduction for heart failure hospitalization, a reduction for cardiovascular deaths. This has to be repeated. Who knows if this is right or if it’s just the play of chance.”
In 2017, results of the CANVAS program were presented and published. As Healio previously reported, patients with type 2 diabetes at high risk for CVD assigned to canagliflozin (Invokana, Janssen) saw a 33% reduction in the risk for HF hospitalization and were 40% less likely to experience renal decline vs. those assigned placebo.
“Now we have two trials with two different -gliflozins that show a substantial benefit,” Braunwald said.
The DECLARE-TIMI 58 trial was presented in 2018 and found that dapagliflozin (Farxiga, AstraZeneca) in patients with type 2 diabetes, compared with placebo, led to a significant 17% RR reduction in the coprimary efficacy endpoint of a composite of CV death or hospitalization for HF.
In 2019, the CREDENCE trial was presented, which found that canagliflozin safely reduced the risk for kidney failure and prevented CV events in patients with type 2 diabetes and chronic kidney disease.
“We have very, very positive results now from four trials with three separate -gliflozins,” Braunwald said.
He said these findings combined led to the first paradigm shift in this area: “SGLT2 inhibitors provide effective management of both cardiac and renal dysfunction in patients with type 2 diabetes.”
SGLT2 inhibition in HF
The focus then shifted to the treatment of HFrEF with dapagliflozin. In 2019, the DAPA-HF trial determined that in patients with HF, with or without diabetes, treatment with this SGLT2 inhibitor reduced the risk for worsening HF and CV death when added to standard therapy.
“What we can say now about SGLT2 inhibition [is that] it shows efficacy in the prevention of heart failure in patients with type 2 diabetes,” Braunwald said. “Secondly, it shows efficacy of treatment of heart failure with reduced ejection fraction in patients with diabetes and in nondiabetics.”
This introduces the second paradigm shift, which relates to the improved management of patients with HFrEF but without diabetes, according to the presentation.
There are less data on the effects of SGLT2 inhibitors in the treatment of patients with HF with preserved ejection fraction, although a paper published in the European Journal of Heart Failure in 2018 found that empagliflozin can lead to direct pleiotropic effects on the myocardium, contributing to improvements in diastolic stiffness and diastolic function independent of diabetic conditions.
“A lot more work needs to be done on that,” Braunwald said. “This is encouraging, but it certainly has not been settled.”
Although there are several favorable effects with SGLT2 inhibitors, there are some unfavorable effects, including genital infections, diabetic ketoacidosis and hypovolemia.
“All of these are controllable, and on the whole, if one watches out for these unfavorable effects, these drugs are extremely well tolerated,” Braunwald said.
Some guidelines have already been updated to reflect the benefits of SGLT2 inhibitors. The European Society of Cardiology guidelines recommend this class to lower the risk for HF hospitalization in patients with type 2 diabetes. The American Diabetes Association also recommends SGLT2 inhibitors in patients with type 2 diabetes and established atherosclerotic CVD, multiple ASCVD risk factors or diabetic kidney disease to reduce the risk for major adverse CV events and HF hospitalization.
Several questions remain in this area, including whether there are differences among individual SGLT2 inhibitors. Other questions focus on their effects on HFpEF and chronic kidney disease without type 2 diabetes. More information is needed on whether the long-term benefits of SGLT2 inhibitors will be sustained.
Call for new subspecialty
Braunwald also called for a diabetocardiology subspecialty.
“There are a huge number of diabetics and a huge number of patients with cardiac disease, but there are not enough diabetologists to handle all of these patients with this combination of illnesses,” Braunwald said. “Therefore, cardiologists are going to have to play a very important role and acquaint themselves with the management of diabetes. This qualifies as a new subspecialty just like onco-cardiology is now a subspecialty between cancer and cardiac disease.”
References:
- Nissen SE, et al. N Engl J Med. 2007;doi:10.1056/NEJMoa072761.
- Oku A, et al. Diabetes. 1999;doi:10.2337/diabetes.48.9.1794.
- Pabel S, et al. Eur J Heart Fail. 2018;doi:10.1002/ejhf.1328.
- Vasilakou D, et al. Ann Intern Med. 2013;doi:10.7326/0003-4819-159-4-201308200-00007.
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Braunwald E. Keynote: SGLT2i and the Birth of Two Paradigm Shifts in Clinical Care. Presented at: Heart in Diabetes CME Conference; Aug. 21-24, 2020 (virtual meeting).
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