sglt2

Dapagliflozin’s HFpEF Benefit Tied to Lower Filling Pressure

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Treatment of patients with heart failure with preserved ejection fraction (HFpEF) with the SGLT2 inhibitor dapagliflozin (Farxiga) for 24 weeks produced significant and beneficial reductions in left-heart filling pressures in a mechanistic, randomized clinical study.

The findings “provide new insight into the mechanisms underlying the favorable clinical effects of dapagliflozin in patients with HFpEF,” Barry A. Borlaug, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. “Elevations in left heart filling pressures at rest and during exercise are fundamental pathophysiologic features of HFpEF,” he noted.

Results from prior studies documented the benefit of dapagliflozin for improving clinical outcomes in patients with HFpEF in the DELIVER trial, and for the related sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance) in the EMPEROR-Preserved trial. The new findings presented by Dr. Borlaug provide evidence from a placebo-controlled, prospective study for one way by which these SGLT2 inhibitors exert this benefit in patients with HFpEF.

The results of his single-center study showed that, in patients with HFpEF who also exhibited “severe” elevations in pulmonary capillary wedge pressure (PCWP) during exercise, 24 weeks of treatment with dapagliflozin led to a significant reduction in PCWP during exercise. The treatment produced an average 6.1–mm Hg drop from baseline compared with control patients who received placebo. A similar pattern occurred when these patients were at rest, when dapagliflozin treatment linked with a significant average reduction in PCWP from baseline of 3.5 mm Hg compared with controls.

Improving a ‘specific and fundamental’ feature of HFpEF

“This fantastic study looked at one of the fundamental aspects of HFpEF,” said John R. Teerlink, MD, designated discussant for the study. “You’ve shown that dapagliflozin targets a specific and fundamental” manifestation of HFpEF by lowering PCWP, said Dr. Teerlink, director of Heart Failure at the San Francisco Veterans Affairs Medical Center.

However, Dr. Teerlink added, the study did not directly address the related question of what physiologic action of dapagliflozin produces this notable drop in PCWP.

“We’re just starting to look at that,” replied Dr. Borlaug, a cardiologist and professor at the Mayo Clinic in Rochester, Minn.

He reported finding an intriguing correlate in the current study linked to the cut in PCWP with dapagliflozin treatment. The SGLT2 inhibitor at a standard daily 10-mg dose produced an average 3.5-kg drop in body weight in the dapagliflozin-treated patients that significantly linked with the changes in PCWP both at rest and during exercise. Dapagliflozin-treated patients also showed a significant reduction from their baseline plasma volume compared with placebo-treated patients, but this “poorly correlated” with the dapagliflozin-linked cuts in PCWP, Dr. Borlaug said.

“I don’t think this means weight loss is the cause of the hemodynamic benefit, but maybe it’s an indicator. When patients [with HFpEF] lose weight, they are in a metabolic state that leads to good changes in hemodynamics,” he suggested. “My guess is that there is probably a combination of many different little things [caused by dapagliflozin treatment of patients with HFpEF] that together result in the 20%-25% relative improvement we see in filling pressure.”

An ‘obese, cardiometabolic’ HFpEF phenotype

The study enrolled patients with HFpEF and a left ventricular ejection fraction of at least 50%, a New York Heart Association functional class of 2 or 3, and a PCWP during exercise of at least 25 mm Hg. Of the 37 evaluable patients, about two-thirds of the patients were women, more than two-thirds were in functional class 3, about 70% were obese, and their average ejection fraction was about 62%. The study excluded patients with HFpEF who also had type 1 diabetes, cardiomyopathy, pericardial disease, or other causes of dyspnea or heart failure.

Dr. Teerlink asked about the generalizability of the findings, as the study cohort seemed to differ in certain respects from the patients enrolled in the DELIVER trial, and because of the many apparently distinct patient phenotypes that exist within the scope of HFpEF.

An “obese, cardiometabolic phenotype” predominated the study cohort, Dr. Borlaug said. “The patients we enrolled look like the HFpEF patients seen in U.S. clinics.” However, he added that “in reality, many [HFpEF phenotypes] coexist in one patient. It’s not that simple,” that every patient with HFpEF can be categorized into a single HFpEF phenotype.

The researchers monitored PCWP invasively with high-fidelity micromanometer catheters.

In Acute Kidney Disease, SGLT2 inhibitors Were All-Around Protective

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Risk of all-cause mortality, MAKE, and MACE were significantly reduced

A computer rendering of a transparent body with the kidneys highlighted.

SGLT2 inhibitors significantly lowered the risk of death, major adverse kidney events (MAKE), and major adverse cardiovascular events (MACE) in people with type 2 diabetes and acute kidney disease, according to a cohort study.

Compared with nonusers, SGLT2 inhibitor users had a 5-year all-cause mortality rate of 9.0% versus 18.7%, which translated into a 31% lower risk of mortality (adjusted HR 0.69, 95% CI 0.62-0.77) over a median 2.3-year follow-up, Vin-Cent Wu, PhD, of the National Taiwan University Hospital in Taipei, and colleagues found.

SGLT2 users also had significantly lower rates for MAKE (9.5% vs 21%) and MACE (13.5% vs 25.8%), which yielded 38% (aHR 0.62, 95% CI 0.56-0.69) and 25% lower risks (aHR 0.75, 95% CI 0.65-0.88), respectively, the researchers noted in JAMA Network Openopens in a new tab or window.

“Given that the current management of acute kidney disease primarily relies on conservative approaches, such as monitoring, medication adjustments, and minimizing kidney-stressing procedures or treatments, there has been a notable absence of targeted pharmacotherapy to offer protection to these patients,” Wu told MedPage Today. He added that this class of drugs has already been well-established to slow kidney function decline and the risk of death in those with chronic kidney disease. At the moment, a few FDA approved SGLT2 inhibitors have diabetes, kidney, and cardiovascular protection indications, including empagliflozin (Jardiance)opens in a new tab or window, dapagliflozin (Farxiga)opens in a new tab or window, and canagliflozin (Invokana).

The current findings add to the argument that this medication class also holds benefits for patients with acute kidney disease, said Wu. “Given the potential contribution of acute kidney disease to the rise in the burdens of MACEs and MAKEs, it is crucial for clinicians to consider using SGLT2 inhibitors to address this growing public health concern.”

Researchers identified 230,366 patients with acute kidney disease (average age 67.1) from the TriNetX global healthcare database who were admitted to targeted healthcare organizations. Among this patient population, only 5,319 (2.3%) were on an SGLT2 inhibitor, which Wu called a “relatively low” number, particularly given the fact that current guidelinesopens in a new tab or window recommend the use of SGLT2 inhibitors in patients with existing kidney disease. “This underscores the need for increased awareness and greater consideration of this critical issue in clinical decision-making,” he pointed out.

Inclusion criteria included a type 2 diabetes diagnosis and having received dialysis during hospitalization. Those who received postdischarge redialysis or who died within 3 months were excluded. MAKEs were defined as redialysis, dialysis dependence, or mortality, and MACEs were defined as cerebral infarction, hemorrhagic stroke, acute myocardial infarction, cardiogenic shock, or mortality.

At baseline, people on SGLT2 inhibitors had slightly higher average HbA1c levels (8.4% vs 7.9%), eGFR (76.9 vs 73.9 mL/min/1.73m2), and BMI (32.3 vs 30.4). More SGLT2 users were also on angiotensin-converting enzyme inhibitors and angiotensin receptor blockers.

Despite the many protective benefits of SGLT2 inhibitors in this population, the researchers did find a higher risk for diabetic ketoacidosis (AHR 1.36, 95% CI 1.00-1.85) and osteoporotic fractures (AHR 1.39, 95% CI 1.04-1.85).

When the researchers looked at specific subgroups, they found the reduction in mortality risk was seen regardless of whether patients were also on insulin, renin-angiotensin aldosterone system blockers, or diuretics. Patients with more advanced kidney disease, no hypertension, and those not taking other diabetic agents had greater reduction of mortality and MAKE risk.

When discussing the thinking behind this study, Wu explained that this group recently conducted a network meta-analysisopens in a new tab or window and found that the use of empagliflozin or dapagliflozin yielded superior renal protection in patients with diabetes and also significantly reduced the risk of acute kidney injury. “The incidence of acute kidney disease following acute kidney injury is approximately 33.6% and it can occur without identifiable preceding acute kidney injury. The development of acute kidney disease is associated with increased risks of chronic kidney disease, dialysis, and mortality.”

The researchers noted that most patients included were white, which could limit how generalizable the findings are to other racial and ethnic groups. Also, the baseline differences in SGLT2 users’ comorbidities and medication use also may have biased the findings.