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As cardiology begins to look at the spectrum of cardiovascular-kidney-metabolic disease, new research in JAMA suggests that CKM treatments might face serious adoption challenges due to the sheer number of Americans who both have the disease and qualify for medications.

It’s well documented that obesity and CKM syndrome continue to rise, but just how many people qualify for treatment has been unclear.
Physicians have a diverse range of pharmaceuticals to choose from for treating CKM, including GLP-1s, SGLT2is, and nsMRAs.

In a search for just how many eligible patients are out there, researchers examined FDA-approved indications across 250M people in the U.S., finding a staggering eligibility burden.

Between 42-61% of adults (~125M) showed indications for one or more CKM medications.
GLP-1 eligibility dominated at 46-56% of all adults, followed by SGLT2is (14-33%) and nsMRAs (1-5%).
Overlapping eligibility for multiple classes was substantial with 12-17% qualifying for both GLP-1s and SGLT2is, while 1-5% met criteria for all three classes.

These findings reveal a massive gap between CKM treatment availability and the population-level implementation required to serve all of these eligible patients.

For example, the 1-5% of Americans (up to 11.7M) who need triple therapy represents a patient population larger than many common chronic diseases like cancer and dementia.
Meanwhile, GLP-1 eligibility alone (up to 137M adults) dwarfs the current prescription patterns when addressing the number of obese Americans.

So where does this CKM treatment disconnect stem from? The answer is likely a combination of the relatively short time that many of these medications have been available and systemic pressures.

Current practice focuses on single-medication therapies and healthcare systems are still catching up on expanding indications, prior authorization navigation, and cost barriers.

There’s also another way to read this data. While the number of patients who are eligible for these medications is immense, that doesn’t mean upping prescriptions is the only way to help them.

Many studies have already shown how healthier diets, more physical activity (even light walks), and weight loss (with or without drugs) can significantly reduce CKM risk.

The Takeaway

This far-reaching analysis looks at over two thirds of the U.S. population and asks the very broad question of “how many people need CKM treatment.” The data it gives us suggests that we’re just getting started when it comes to pharmaceutically treating CKM on the population level, even if more drugs shouldn’t be the only option.

Amgen’s PCSK9 inhibitor Repatha (evolocumab) is facing scrutiny after a reassessment of its FOURIER late-stage trial data revealed that the biologic may be associated with an increased risk of cardiovascular death.

The FOURIER trial laid the foundation for Repatha’s regulatory approval. The reanalysis, published in the BMJ, has identified several inconsistencies between the 2017 NEJM publication of FOURIER’s primary results and a more detailed Clinical Study Report (CSR). In cases of discrepancy between the sources, an independent committee blindly “readjudicated and restored” the cause of death according to the information in the CSR narratives.

The reanalysis found that the number of deaths of cardiac origin was higher in the evolocumab group than the placebo group (113 vs. 88), although the relative increase in CV mortality was still non-significant (RR 1.20, p=0.13).
The authors argue that the reanalysis raises the possibility that evolocumab might have specific adverse cardiac effects, a hypothesis “consistent with pharmacovigilance reports” (FAERS, Eudravigilance or VigiAccess databases), but inconsistent with the FOURIER trial finding that evolocumab decreased non-fatal myocardial infarctions.
Specifically, the CSR contained a higher number of deaths due to myocardial infarction (36 vs. 25) and cardiac failure (31 vs. 16) than the NEJM report.

These findings have caused a stir in the medical community, with reactions ranging from confusion and surprise to others pointing out that the “readjudication and restoration” process may not have been more accurate than the original adjudication process, and did not even yield significant findings. However, authors of the reanalysis point out that the original investigation was terminated early, and had the investigation been carried out over the full 56-month follow-up, evolocumab-related CV mortality may have reached statistical significance.

This new scrutiny emerges while Amgen is in a patent fight over Repatha, arguing to revive patents protecting Repatha and to block the sale of Praluent (alirocumab), a similar PCSK9 inhibitor created by Sanofi.

The Takeaway

Discrepancies between CSRs and peer-reviewed publications are actually fairly common, and the particular discrepancies noted in the reanalysis do not dramatically change the takeaways from the original FOURIER publication. That said, this type of scrutiny is never welcome, and at the very least, the study points to the importance of data transparency.

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