Pop Goes the Pillbox: Will Polypharmacy Problems Limit the Adoption of SGLT2 Inhibitors?
For many individuals with heart failure, the day begins and ends with a trusted companion: the pillbox. Typically older and on multiple medications to treat heart failure on top of a range of comorbidities, these patients must jockey a dozen or more pills a day.
“Patients complain about polypharmacy, and we know that compliance, potential side effects and unanticipated drug interactions are important issues,” says James Fang, MD, chief of cardiovascular medicine at the University of Utah School of Medicine.
Against that backdrop, how will the latest star to burst onto the heart failure stage—sodium-glucose cotransporter 2 (SGLT2) inhibitors, with their positive results in both heart failure and type 2 diabetes—play out? Will cardiologists readily incorporate them into their clinical practice? Or will the SGLT2 inhibitors force cardiologists to confront the broader issues of how many pills are too much for their heart failure patients, and whether patients can even afford these medications?
A cautionary note is provided by the last breakthrough drug for patients with heart failure with reduced ejection fraction: the combination valsartan and sacubitril, an angiotensin receptor neprilysin inhibitor (ARNI). Three years after the 2014 PARADIGM-HF trial reported the benefits of this medication, it was estimated that less than 15 percent of eligible patients were actually taking it, according to an editorial authored by Fang in the New England Journal of Medicine (2019;381:2063-4).
“As a provider myself,” Fang told CVB, “a significant barrier to my writing prescriptions for sacubitril/valsartan has been cost. The uptake of this drug would have been a lot faster and greater had it not been priced this way. The hassle for providers and patients has gotten better, but we’re still not there.”
With its price tag of up to $500 a month without insurance, the SGLT2 inhibitor dapagliflozin (Farxiga, AstraZeneca) could face similar obstacles—despite its impressive outcomes in heart failure patients both with and without diabetes in the DAPA-HF and DEFINE-HF clinical trials (N Engl J Med 2019;381[21]:1995-2008; Circulation 2020;141[2]:90-9; Circulation 2019;140[18]:1463-76).
Saint Luke’s Mid America Heart nstitute, Kansas City, Mo.
Courtesy of the American Heart Association.
“Sacubitril/valsartan was a new, first-in-class compound that few clinicians had experience with at the time,” points out Mikhail Kosiborod, MD, director of cardiometabolic research at Saint Luke’s Mid America Heart Institute in Kansas City, Mo., and chair of DEFINE-HF. “The SGLT2 inhibitors, on the other hand, have been used for diabetes treatment for years and in millions of patients worldwide. It may take some time for cardiologists to get used to them, but I believe they’ll be incorporated as an add-on to current guideline-directed medical therapy in heart failure with reduced ejection fraction.”
The guidelines for cardiovascular risk reduction in type 2 diabetes are being reviewed by the ACC under its Expert Consensus Decision Pathway while the FDA considers on a fast-track basis an indication for dapagliflozin to slow the progression of kidney failure and prevent cardiovascular and renal death in patients with chronic kidney failure.
The additive impact of SGLT2 agents
In light of the polypharmacy challenge, could the multi-purpose SGLT2 agents supersede the ARNIs or other drugs that have become accepted parts of the panoply of care for heart failure? Douglas Mann, MD, chief of the division of cardiology at Washington University School of Medicine in St. Louis, doesn’t believe there is sufficient evidence now to make that determination. “I think they will work their way into the armamentarium as first-line drugs on top of standard medical therapy,” he says, “but whether they will be used instead of, or on top of, sacubitril/valsartan is speculation at this point.”
James Januzzi, MD, a cardiologist at Massachusetts General Hospital and professor of medicine at Harvard Medical School, issued a “resounding no” when asked if the SGLT2 inhibition drugs should serve as an alternative or replacement for other heart failure medications. “There’s a huge amount of enthusiasm and optimism among cardiologists for this easily used class of medications,” he elaborates. “They typically exert their benefits at the lowest doses they’ve been tested at, come with minimal side effects and are additive to the armamentarium of therapies for heart failure that already exists.”
Januzzi advocates that cardiologists for now stick to the clinical guidelines, which specify the SGLT2 inhibitors should be used for patients with heart failure from reduced rejection fraction with hemoglobin A1c greater than 7 percent. “With further data from studies examining the role of SGLT2 inhibitors in heart failure with reduced ejection fraction, it’s likely we’ll add these drugs to the usual care of these patients, even those without diabetes,” he predicts.
The finding from recent trials that SGLT2 inhibitors are effective in heart failure patients either with or without diabetes has prompted speculation that some cardiologists would prescribe them, particularly for patients not responding to standard therapy, irrespective of diabetes. That scenario, however, would require off-label usage, foreclosing reimbursement and thus putting the drug out of financial reach of most patients.
A more relevant question for cardiologists at this early stage seems to be over the use of SGLT2 inhibition as a first-line therapy for patients at risk of heart failure because of their diabetes—the so-called hypertensive diabetics. “We now have strong data suggesting that these agents are very effective in preventing heart failure in stage A patients who don’t yet have clinically recognized heart failure,” Kosiborod says. This approach takes on particular meaning, he adds, inasmuch as cardiovascular and kidney disease are the two most common and potentially deadly complications from diabetes. SGLT2 inhibitors have proven effective against both.
University of Colorado School of Medicine, Aurora Courtesy of the American Heart Association.
With the toolbox for treating heart failure now fuller than ever, another question arises over appropriate sequencing of drugs—a sensitive issue especially for heart failure patients just beginning treatment. “It’s generally a bad idea to start them on four drugs simultaneously because of possible side effects,” notes Larry Allen, MD, MHS, medical director of Advanced Heart Failure at the University of Colorado School of Medicine. “We need to be thinking about sequencing that makes sense for each patient, and I’d suggest this means considering an SGLT2 inhibitor early in the sequencing process. The cumulative effect of these drugs in combination with others can be huge in terms of health outcomes for patients.”
Addressing polypharmacy & cost issues
However important these issues might be, they take a back seat to the challenges of affordability and polypharmacy in the minds of some experts. As Mann puts it, “Polypharmacy is a problem, and SGLT2 inhibitors are going to add to it. Going forward, the field needs to figure out what is the appropriate constellation of drugs. It may be that certain patients do better on just an ACE inhibitor or beta-blocker along with an SGLT2 inhibitor, while others need to be on four drugs. We just don’t know yet.”
Acknowledging there is a limit to the number of drugs heart failure patients can reasonably be expected to take, Kosiborod draws a comparison with another devastating disease. “We don’t ask the same question of people with cancer,” he argues. “If the risk of dying of heart failure is the same as someone with advanced lung cancer, wouldn’t you want them to live longer and have a better quality of life, even if it means being on multiple medications?” He hastens to add, though, “What we absolutely should be doing is examining each patient’s medication list and eliminating those that are nonessential.”
At the University of Utah School of Medicine’s heart failure program, clinical pharmacists have become an increasingly important part of the healthcare delivery team, which conducts a routine review of each patient’s medications to get a better handle on compliance, drug interactions and cost. “It’s a little disingenuous for a physician to discharge a patient on 20 pills a day,” says Fang. “Do we really think they’re going to pick up all of them and then take them?”
Medication reconciliation is also top of mind for physicians at Massachusetts General Hospital’s heart center. They streamline treatment by employing a team-based approach that addresses not just heart failure but also medical comorbidities, explains Januzzi. “In clinic the other day,” he recalls, “I deprescribed numerous medications for my heart failure patients based on the fact they were tangential to their overall healthcare plan, and in some cases they were redundant. This kind of medication scrutiny is critically important at every patient visit.”
As part of that vigilance, the Massachusetts General team is focused on the lifelong education of each heart failure patient. This may include, for example, recommending the use of pillboxes or working with a pharmacy to pre-package multiple medications to help with compliance. The team also works to address the cost barriers of medications that patients may be too embarrassed to bring up in conversations with their providers.
“We’ve been able at our heart center to almost routinely get higher cost medicines for our patients covered at much lower levels,” reports Januzzi. “In the heart failure space, it’s going to be about implementation science as we move into the next decade—in other words, understanding how all these drugs work together and how we as physicians can best deliver them to our patients most in need.”