Empagliflozin shows potential to reduce heart disease

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A new study from St. Michael’s Hospital in Toronto, Canada shed lights on how a class of medications that help regulate blood sugar for patients with Type 2 diabetes can also protect against heart disease.

The findings from the EMPA-HEART CardioLink-6 Trial, presented today at the ESC Congress 2019, organized by the European Society of Cardiology, and simultaneously published in Cell Metabolism, focus on the effect of a diabetes medication – empagliflozin – on cell repair in blood vessels and the resulting risks of heart disease.

Empagliflozin is a medication that falls under a category of drugs called SGLT2 inhibitors, which lower blood sugar.

The research suggests that circulating progenitor cells – which are found in bone marrow and play a role in heart health – along with inflammatory cells are regulated with this diabetes medication.

For patients who have diabetes and are at risk of heart disease, such medications may provide heart protection by relieving damaged cells that would otherwise perpetuate heart disease by causing faulty vessel repair.

“We have seen large-scale clinical trials giving us clear evidence that SGLT2 inhibitors can also protect our patients who have diabetes from heart disease,” said Dr. Subodh Verma, a cardiac surgeon and scientist at the Keenan Research Centre for Biomedical Science (KRCBS) of St. Michael’s Hospital. “Before our study, it wasn’t known why this was happening.”

According to the World Health Organization, an estimated 1.6 million deaths were caused by diabetes in 2016.

It is a major cause of blindness, kidney failure, heart attacks, stroke and lower limb amputation.

Heart disease is a major concern for people with diabetes as they often have compromised blood vessel repair, making them more susceptible to cardiovascular issues.

The team at St. Michael’s collaborated with Dr. David Hess, an associate professor at Western University’s Schulich School of Medicine & Dentistry and a scientist at Robarts Research Institute. Dr. Hess is an expert in the identification and quantification of blood vessel progenitor cells.

Using blood samples from the EMPA-HEART CardioLink-6 Trial, Dr. Hess was able to show that in diabetes, regenerative progenitor cells were reduced.

In patients who took empagliflozin, however, these progenitor cells were restored.

“We found that in people with diabetes, not only were beneficial progenitor cells increased but we saw indications of reduced inflammation and oxidative stress, which can also contribute to cardiovascular disease,” said Dr. Hess.

For patients with diabetes, this is an important step forward to reduce their risk of heart disease, Dr. Verma said.

The team at St. Michael’s included: Dr. Verma; Dr. Rotstein; Dr. David Mazer, an anesthesiologist and scientist at the KRCBS; Dr. Mohammed Al-Omran, a heart surgeon and scientist at the KRCBS; Dr. Kim Connelly, a cardiologist and scientist at the KRCBS; Dr. Andrew Yan, a cardiologist; and Dr. Lawrence Leiter, an endocrinologist and scientist at the Li Ka Shing Knowledge Institute.

The researchers say these novel findings may provide the basis for new therapies for patients who have heart disease complicated by diabetes.

Journal information: Cell Metabolism
Provided by St. Michael’s Hospital


Background:

In the EMPA-REG OUTCOME trial (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) in patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease, in comparison with placebo, empagliflozin reduced the risks of 3-point major adverse cardiovascular events (3-point MACE), cardiovascular and all-cause death, and hospitalization for heart failure. We investigated whether these effects varied across the spectrum of baseline cardiovascular risk.

Methods:

Cardiovascular death, all-cause mortality, 3-point MACE, and hospitalization for heart failure in the pooled empagliflozin and placebo groups were analyzed in subgroups by prior myocardial infarction and stroke at baseline, and by estimated baseline cardiovascular risk based on the 10-point TIMI (Thrombolysis In Myocardial Infarction) Risk Score for Secondary Prevention.

Results:

Of 7020 patients who received the study drug, 65% had a prior myocardial infarction or stroke, and 12%, 40%, 30%, and 18% were at low, intermediate, high, and highest estimated cardiovascular risk according to TIMI Risk Score for Secondary Prevention (≤2, 3, 4, and ≥5 points, respectively). In the placebo group, 3-point MACE occurred during the trial in 7.3%, 9.4%, 12.6%, and 20.6% of patients at low, intermediate, high, and highest estimated baseline risk, respectively. Relative reductions in risk of cardiovascular death, all-cause mortality, 3-point MACE and hospitalization for heart failure with empagliflozin versus placebo were consistent in patients with and without prior myocardial infarction and/or stroke and across subgroups by TIMI Risk Score for Secondary Prevention at baseline (P>0.05 for randomized group-by-subgroup interactions).

Conclusions:

Despite all patients having atherosclerotic cardiovascular disease, patients in EMPA-REG OUTCOME demonstrated a broad risk spectrum for cardiovascular events. Reductions in key cardiovascular outcomes and mortality with empagliflozin versus placebo were consistent across the range of cardiovascular risk.

Clinical Trial Registration:

URL: https://www.clinicaltrials.gov. Unique identifier: NCT01131676.

Keywords: cardiovascular diseases, carotid artery diseases, death, sudden, cardiac, diabetes mellitus, type 2, sodium-glucose transporter 2

Clinical Perspective

What Is New?

  • Among patients with type 2 diabetes mellitus and prevalent atherosclerotic cardiovascular disease, there is a 10-fold variation in future cardiovascular (CV) risk.
  • In this group, individuals with or without a prior atherothrombotic event, and across the spectrum of predicted risk derived from baseline characteristics, have a similar reduction in CV mortality and hospitalization for heart failure with the sodium glucose cotransporter 2 inhibitor, empagliflozin.

What Are the Clinical Implications?

  • The reduction of CV events with empagliflozin, in patients with type 2 diabetes mellitus and known atherosclerotic CV disease extends across the spectrum of underlying CV risk, and is not confined to patients at the highest risk.
  • Empagliflozin should be considered in patients with type 2 diabetes mellitus and all forms of atherosclerotic CV disease to reduce CV mortality and hospitalization for heart failure.

Cardiovascular disease presents as a range of phenotypes that starts with the presence of multiple risk factors and progresses, largely because of atherothrombotic events, to myocardial infarction (MI), heart failure (HF), and death.1,2 However, myocardial dysfunction, HF, and cardiovascular death can occur independently of atherothrombosis, especially in patients with diabetes mellitus.3,4 Patients with type 2 diabetes mellitus (T2DM) are considered to be at very high risk for future adverse cardiovascular events.5,6 However, recent data show a broad spectrum of cardiovascular risk exists even in patients with cardiovascular disease and diabetes mellitus.7

Several stratification methods have been developed to predict the risk of primary cardiovascular events in individuals with cardiovascular disease risk factors8,9 and the risk of recurrent cardiovascular events in individuals with recent acute coronary syndrome.1012 The Thrombolysis In Myocardial Infarction (TIMI) Risk Score for Secondary Prevention (TRS 2°P) is a risk stratification tool developed to predict recurrent cardiovascular events in patients with a history of MI13 and validated in other populations, including patients with stable atherosclerotic cardiovascular disease (ASCVD).14,15 The original version conferred 1 point for each of 9 cardiovascular risk factors: HF, hypertension, age ≥75 years, diabetes mellitus, prior stroke, prior coronary artery bypass graft surgery, peripheral vascular disease, estimated glomerular filtration rate <60 mL·min1·1.73 m2, and current smoking.13 To stratify risk in patients with stable ASCVD, the score was adapted to include prior MI as a risk factor to make a maximum 10-point score.15 The 10-point TRS 2°P was evaluated in patients with T2DM and high cardiovascular risk with data from the SAVOR TIMI 53 trial (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53)7 and validated for the prediction of major adverse cardiovascular events (MACE) using the cohort of patients with T2DM and high cardiovascular risk from the REACH observational registry (Reduction of Atherothrombosis for Continued Health).7,16

In the EMPA-REG OUTCOME trial (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) in patients with T2DM and ASCVD, the sodium glucose cotransporter 2 inhibitor empagliflozin given in addition to standard of care reduced the risk of 3-point MACE (composite of cardiovascular death, nonfatal MI, or nonfatal stroke) by 14%, cardiovascular death by 38%, all-cause death by 32%, and hospitalization for heart failure (HHF) by 35% in comparison with placebo.17 ASCVD was defined as a prior atherothrombotic event (MI or stroke) and other vascular manifestations of ASCVD (multivessel coronary artery disease; single-vessel coronary artery disease with ischemia and unstable angina ≤12 months before consent or occlusive peripheral artery disease).17

Currently, it is uncertain whether patients with diabetes mellitus with other ASCVD risk factors yet no prior proven ASCVD derive cardiovascular benefits from sodium glucose cotransporter 2 inhibition. In the CANVAS trials program (Canagliflozin Cardiovascular Assessment Study), the subgroup with no ASCVD had no apparent reduction in risk for the primary outcome in comparison with patients with prevalent ASCVD at trial entry, with a P value for interaction of 0.18. Consequently, it is important to determine whether patients at lower risk of cardiovascular events have a reduction of risk for cardiovascular outcomes with empagliflozin.

In the present analyses, we (1) assessed the spectrum of predicted and observed cardiovascular risk among patients with T2DM and prevalent ASCVD enrolled in the EMPA REG OUTCOME trial, and (2) investigated whether the effects of empagliflozin on cardiovascular outcomes and mortality varied across the spectrum of cardiovascular risk at baseline. We assessed the risk of these outcomes in subgroups of patients (1) with and without a prior atherothrombotic event (MI or stroke) at baseline, and (2) stratified by baseline cardiovascular risk estimated using the 10-point TRS 2°P.

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