A Pillared Approach: A Suite of Therapies for a Spectrum of Metabolic Disease

For nearly a decade now, an evolution in the management of metabolic conditions has been happening in plain sight.

At a time when US public health systems are experiencing a historic burden of metabolic disease, including obesity, type 2 diabetes, heart failure, and chronic kidney disease, this evolution, which includes revelations of benefits from established classes and the introduction of new agents, comes at a time when health systems are in dire need.

What began as a revelation of the benefits of antihyperglycemic agents, has led to a reform in management approaches many specialists could never have imagined witnessing in their lifetime, with heart failure with reduced ejection fraction (HFrEF) becoming the first battleground. Led by the SGLT2 inhibitor class, the rapid advent of a new approach to care has led to the adoption of a “pillared” approach to care.^1,2,3

Now, as the community nears 2025, these therapies, namely SGLT2 inhibitors, incretin therapies, and nonsteroid mineralocorticoid receptor agonists (nsMRA), have proven their worth in a new frontier where effective therapies had eluded the community for decades—heart failure with preserved ejection fraction (HFpEF).

Muthiah Vaduganathan, MD
Credit: Brigham and Women's Hospital

“I think, traditionally, HFpEF has been viewed as a chronic disease with slower disease progression, perhaps low clinical event rates and low mortality rates,” explained Muthiah Vaduganathan, MD, MPH, Center for Cardiometabolic Implementation Science at Brigham and Women's Hospital and a member of the FINEARTS-HF investigatory team, in an interview with HCPLive Cardiology. “But what we're recognizing is that many phenotypes of HFpEF actually do progress rapidly, and so upfront initiation of therapies to attenuate that risk of disease progression is of high importance.”

Following the historic HFrEF trials, which contributed to the approvals of dapagliflozin (Farxiga) and empagliflozin (Jardiance), the heart failure community’s sights were already set on HFpEF as the landmark EMPEROR-Preserved and DELIVER trials were already underway. Those on the frontlines of research waited with bated breath after the results of the SOLOIST-WHF trial showed benefit in heart failure with the SGLT1/2 sotagliflozin (Inpefa) among a patient population with type 2 diabetes and decompensated heart failure.^1,2,3

In February 2022, empagliflozin became the first SGLT2 inhibitor to receive approval from the FDA for heart failure across the spectrum of ejection fraction. In May 2023, dapagliflozin would get its own nod from the FDA for HFpEF and sotagliflozin received approval for an indication that includes the full range of left ventricular ejection fraction.^1,2

Deepak Bhatt, MD, MPH, MBA
Credit: Mount Sinai

Still, even while celebrating these approvals and the ongoing revolution in care, the community recognized the need for more therapies. Much to their delight, this wait would not be decades, but less than 2 years before new classes began to evidence their benefits in this condition.

“It's a totally new world in HFpEF,” said Deepak Bhatt, MD, MPH, MBA, principal investigator of the SOLOIST-WHF as well as the director of Mount Sinai Heart and the Dr. Valentin Foster Professor of Cardiovascular Medicine at the Icahn School of Medicine, in an interview with HCPLive Cardiology. “It was the SGLT2 inhibitors that open the door for therapies that actually work, and are evidence based in heart field preserved ejection fraction.”

Incretins and nsMRAs in HFpEF

Few stories in healthcare have drawn more attention in recent years from the medical community as the rise of SGLT2 inhibitors, except for the craze surrounding GLP-1 receptor agonists and, subsequently, dual incretin therapies.

Although topline data gave insight into the effects observed in the overall trial at the end of 2023, the STEP-HFpEF program gave the heart failure community a glimpse into the potential of incretin therapies, with results demonstrating a benefit on quality of life among patients with obesity-related HFpEF. Later, STEP-HFpEF DM would solidify these benefits in an additional patient population defined by the presence of type 2 diabetes in addition to obesity-related HFpEF.⁴

With these trials and the SELECT trial, which included a subgroup of patients with heart failure, evidencing the holistic benefits of semaglutide use in patients in at-risk populations, many in the community looked ahead to the SUMMIT trial for confirmatory evidence of benefits on event-based outcomes in HFpEF populations.

A phase 3 trial of more than 700 adults, SUMMIT, which was presented at the American Heart Association Annual Scientific Sessions 2024, concluded use of tirzepatide (Mounjaro) was associated with a 38% reduction in heart failure hospitalization or cardiovascular death relative to placebo therapy—establishing the idea of incretin therapies as a foundational party of HFpEF management in the future.⁵

While the excitement around GLP-1 RAs, namely semaglutide, was reaching a fever pitch, Bayer and their nsMRA finerenone, which received approval for people with type 2 diabetes and chronic kidney disease in July 2021, had their sights set on an additional indication and patient population.⁶

At the European Society of Cardiology Congress 2024, full results of the FINEARTS-HF trial demonstrated use of finerenone was associated with a statistically significant 16% relative reduction in the rate of primary outcome events compared with placebo therapy. These effects were further evidenced during the same session, where Vaduganathan presented data from FINEHEART, which was a pooled analysis of the FINEARTS-HF, FIGARGO-DKD, and FIDELIO-DKD trials. ⁶

Ankeet Bhatt, MD, MBA
Credit: American Heart Association

Now, as the community approaches 2025, it finds itself in a similar position as it had just a few years ago—a collection of therapeutic classes showing distinct benefits in a difficult-to-treat population contributing to a significant need for education on optimal implementation in the form of a pillared approach.

“We also may be developing is a suite of therapies, and this is what I'm hopeful for, that actually modify the entire condition,” said Ankeet Bhatt, MD, MBA, ScM, a research scientist at Kaiser Permanente Northern California and an associate physician at Kaiser San Francisco Medical Center, in an interview at AHA 2024. “As a clinician and as an investigator, it makes me interested to know about whether we as a community have created distinct disease states, but, in fact, they may be all driven in part by certain common pathways that we're just learning how to modify across all these disease states now.”

Beyond Heart Failure

As Ankeet Bhatt alluded to, this revolution and the adoption of a pillared approach to care is not entirely unique to heart failure and has been, at least in part, occurring in similar fashion, albeit different order, within the management of chronic kidney disease in type 2 diabetes.

Just as with discussions in HFrEF, the SGLT2 inhibitor class, at least at face value, can be credited as the catalysts of much of this revolution in chronic kidney disease in type 2 diabetes.

As the heart failure community was celebrating approval of dapagliflozin as the first SGLT2 inhibitor approved in HFrEF in May 2020, nephrology had its sights set on their own new era in management led by the same class of therapy—as AstraZeneca had already announced the discontinuation of DAPA-CKD in March 2020 and the EMPA-Kidney trial, which was still ongoing, would soon offer confirmatory effects of a potential class benefit. Both dapagliflozin and empagliflozin would go on to receive approvals in April 2021 and September 2023, respectively.1,2,3

Nearly in lockstep, finerenone received its aforementioned approval for reducing risk of serious kidney and heart complications in adults with chronic kidney disease associated with type 2 diabetes in July 2021, less than 3 months after the approval of dapagliflozin for HFrEF. Now, a pair of medical specialties, which were once handcuffed by a lack of therapies, found itself discussing sequencing of therapies beyond RAAS inhibition.⁶

Brendon Neuen, MBBS, PhD
Credit: X.com

In 2024, results would be presented at the 61st European Renal Association Congress topline data from the landmark FLOW trial, which demonstrated the benefits of semaglutide 1.0 mg in people with type 2 diabetes and chronic kidney disease—further cementing their role in cardiorenal protection among patients with type 2 diabetes.⁷

“These different therapies all target different pathways, and it's interesting that we now have four pillars of therapy for diabetic kidney disease, much in a similar way to how we have pillars of therapy for heart failure,” said Brendon Neuen, MBBS, PhD, TITLE, in an episode of Diabetes Dialogue. “It's very interesting, at least to me, that many of these pillars are actually similar. This convergence of guideline-directed therapy across the disease states across cardio, kidney, metabolic health, and that, I think, is the big story here, that the 4 pillars of guideline-directed therapy are actually converging across different disease states.”

A signal of the changing landscape of care for cardiovascular-kidney-metabolic disease, in early December 2024 the American Heart Association disclosed its guideline writing committee was composing the latest edition of their cardio kidney metabolic health for release in Q1 2026, which would be less than 3 years since their initial Presidential Advisory on the topic.⁸

References:

1. Campbell P. FDA expands Dapagliflozin label to include reducing risk of CV death in heart failure. HCP Live. May 9, 2023. Accessed December 6, 2024. https://www.hcplive.com/view/fda-expands-dapagliflozin-label-to-include-reducing-risk-of-cv-death-in-heart-failure.
2. Campbell P. Empagliflozin (Jardiance) receives CKD approval from US FDA. HCP Live. September 28, 2023. Accessed December 6, 2024. https://www.hcplive.com/view/empagliflozin-jardiance-receives-ckd-approval-from-us-fda.
3. Campbell P. FDA approves Sotagliflozin for treatment of heart failure. HCP Live. May 26, 2023. Accessed December 6, 2024. https://www.hcplive.com/view/fda-approves-sotagliflozin-for-treatment-of-heart-failure.
4. Campbell P. Step HFPEF DM: Semaglutide 2.4 mg improves functional status, symptoms in patients with diabetes, HFPEF. HCP Live. April 7, 2024. Accessed December 6, 2024. https://www.hcplive.com/view/step-hfpef-dm-semaglutide-2-4-mg-improves-functional-status-symptoms-in-patients-with-diabetes-hfpef.
5. Campbell P. Summit trial proves Tirzepatide’s benefit in HFPEF with obesity. HCP Live. November 16, 2024. Accessed December 6, 2024. https://www.hcplive.com/view/summit-trial-proves-tirzepatide-s-benefit-in-hfpef-with-obesity.
6. Campbell P. Finearts-hf: Finerenone could find role as second pillar in HFMREF/HFPEF. HCP Live. September 2, 2024. Accessed December 6, 2024. https://www.hcplive.com/view/finearts-hf-finerenone-could-find-role-as-second-pillar-in-hfmref-hfpef.
7. Campbell P. Flow trial fortifies SEMAGLUTIDE’s role in chronic kidney disease and type 2 diabetes. HCP Live. May 24, 2024. Accessed December 6, 2024. https://www.hcplive.com/view/flow-trial-fortifies-semaglutide-s-role-in-chronic-kidney-disease-and-type-2-diabetes.
8. American Heart Association. Upcoming guideline publication schedule. professional.heart.org. Accessed December 6, 2024. https://professional.heart.org/en/guidelines-and-statements/upcoming-guideline-publication-schedule.