Heart failure and type 2 diabetes are exquisitely intertwined. Their shared pathophysiology can accelerate debilitating outcomes for patients that clinicians struggle to prevent and treat.
People with type 2 diabetes are two to four times more likely to develop heart failure (HF) than a person without type 2 diabetes, according to data from the American Heart Association (AHA). But HF itself is also a risk factor for type 2 diabetes, with insulin resistance often the mechanism linking the two.
“It is a vicious cycle — insulin resistance can lead to diabetes, diabetes increases the risk for HF, and HF can then exacerbate insulin resistance — makingdiabetes more difficult to manage,” Silvio E. Inzucchi, MD, professor of medicine at Yale University School of Medicine and Yale-New Haven Hospital, told Endocrine Today. “This is a really interesting bidirectional relationship between diabetes and HF.”
Photo courtesy of Silvio E. Inzucchi. Printed with permission.
Until recently, cardiologists, and to some extent, endocrinologists managing diabetes, had few good options for these patients, apart from angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, angiotensin receptor-neprilysin inhibitor drugs, beta-blockers, mineralocorticoid antagonists and diuretics. The treatment landscape is quickly evolving.
Since the 2015 landmark EMPA-REG OUTCOME trial of the SGLT2 inhibitor empagliflozin (Jardiance, Boehringer Ingelheim and Eli Lilly), data have revealed surprises for a class of diabetes drugs designed initially to lower blood glucose.
Instead, SGLT2 inhibitors may hold the keys to not just preventing HF, but treating existing HF, even for people without diabetes.
“The EMPA-REG OUTCOME trial changed the field dramatically when it came out in 2015,” Deepak L. Bhatt, MD, MPH, executive director of interventional cardiovascular programs at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, told Endocrine Today. “Those results showed large and significant reductions for hospitalization for HF, and for that matter, also in CV death. That changed the way we were conducting diabetes trials. Until then, the goal was just to show diabetes drugs were safe from a CV standpoint, not increasing [myocardial infarction] risk. The bar was raised after that trial — to actually influence CV outcomes.”
In the 6 years since EMPA-REG OUTCOME, SGLT2 inhibitors have emerged as foundational pillars in the treatment of people with HF. New trial data show the class benefits extend to people with and without diabetes, and several studies are currently evaluating SGLT2 inhibitors for people with HF with preserved ejection fraction (HFpEF), a population with substantially fewer effective treatment options.
“I keep hearing the words ‘pillars of care’ with respect to SGLT2 inhibitors and diabetes with HF, and that should be a pillar of care,” Ileana L. Piña, MD, MPH, FAHA, FACC, professor of medicine at Wayne State University and clinical professor of medicine at Central Michigan University, told Endocrine Today. “If you are prescribing an ACE inhibitor and a beta-blocker, why not start the SGLT2 inhibitor at the same time? You don’t have to worry about blood pressure. You don’t have to worry about heart rate. The side effects are minimal, and it is once a day. Why wait?”
‘This is backward science’
When SGLT2 inhibitors were first assessed in large trials as part of an FDA requirement to prove CV safety for any new diabetes agent, most researchers hoped for just that — CV safety.
“This was during an era where there were concerns about thiazolidinediones and their clear, negative impact on HF risk, and then also the saxagliptin (Onglyza, AstraZeneca) study SAVOR-TIMI 53, which found a surprising increased risk for hospitalization for HF from a DPP-IV inhibitor that had been considered pretty bland on everything in terms of CV risk, neither good nor bad,” Inzucchi said. “There had also been some observational data that suggested even insulin itself could be deleterious for HF risk, although that has since been disproven. There was a lot of concern in the diabetes community in the first decade of the 21st century that we needed a medication that not only would show safety for hospitalization for HF, but actually improved rates for hospitalization for HF.”
For all the CV outcomes trials, the primary outcome was major adverse CV events, typically defined as nonfatal stroke, nonfatal MI and CV death. However, trialists prospectively collected HF outcomes and centrally adjudicated them.
“In the early trials we were doing, which were focused on making sure new diabetes drugs were not increasing the risk for heart attack, there was actually a lot of HF occurring. Rates for HF were at least as high as the risk for MI,” Bhatt said. “It turned out HF was much more common than we appreciated in patients with diabetes who did not have overt HF to begin with. Therefore, it became important to try to find ways to reduce that risk for HF.”
The data, beginning with EMPA-REG OUTCOME, would speak for itself. Across all CV outcome trials for empagliflozin, dapagliflozin (Farxiga, AstraZeneca), canagliflozin (Invokana, Janssen) and ertugliflozin (Steglatro, Merck), hospitalization for HF was significantly reduced by 30% to 35% among people who received the drugs. The onset of benefit was rapid, with curves among those who received the drug vs. those who received placebo separating dramatically within a few weeks.
The numbers left researchers searching for a mechanism that could explain such substantial benefit.
“A lot of scientists say this is backward science, going from the bedside to the bench,” Darren K. McGuire, MD, MHSc, professor of medicine in the division of cardiology, Dallas Heart Ball Chair for Research on Heart Disease in Women and Distinguished Teaching Professor at the University of Texas Southwestern Medical Center, Dallas, told Endocrine Today. “We are taking an observation that has been consistent across trials, across different patient populations and across different compounds in the class, and we are going back to the science to try and figure out what is going on.”
Finding the why
Initially, there were many glucose-based hypotheses offered to explain the surprising HF benefits observed, McGuire said. One such theory: If a patient is hyper-filtering glucose — and hyper-reclaiming glucose — they are also hyper-reclaiming sodium.
“That sets off a whole cascade of kidney mechanisms that modify systemic physiology,” McGuire said. “HF stimulates the renin angiotensin aldosterone system and the sympathetic nervous system, increases BP, may also increase heart rate, expands plasma volume. There are all these pernicious effects. When you block those, you can restore the kidney back to normal physiology. There is a lot of plausibility to the idea of a secondary kidney-mediated mechanism.”
That premise, however, requires something to be “broken” to fix, McGuire said. Subsequent SGLT2 inhibitor trials performed specifically with patients with established HF, like DAPA-HF and EMPEROR-Reduced, would demonstrate a comparable HF effect for dapagliflozin and empagliflozin independent of diabetes status. When it came to HF benefit, a class of drugs developed for type 2 diabetes worked just as well for people who did not have diabetes.
“[SGLT2 inhibitors] do act as diuretics, but it is believed that the body adapts to that early effect after a while,” Bhatt said. “While it is still controversial, that is not believed to be the dominant mechanism of action. However, it probably does account for at least some of the benefit.”
Inzucchi said researchers observed that the typical mechanisms that kick in with the use of traditional diuretics, such as activation of the sympathetic nervous system and the renin angiotensin system, may not occur when an SGLT2 inhibitor is used — at least not to the same extent.
“It is almost as if the body is tricked into not having this typical, but ultimately counterproductive, response when plasma volume is reduced with an SGLT2 inhibitor as opposed to conventional diuretics,” Inzucchi said. “But there is also evidence for other factors that may be playing a role.”
Other theories persist. Some suggest SGLT2 inhibitors cause a shift in energy utilization by the heart or an increase in the production of ketone bodies by the liver, better “fueling” the heart.
Still other theories relate to direct effects on the heart.
“There are studies looking at the left ventricular muscle function and direct heart effects, not just from a volume overload standpoint,” Savitha Subramanian, MD, associate professor in the division of metabolism, endocrinology and nutrition and medical director of the lipid clinic at the University of Washington School of Medicine, told Endocrine Today. “There may be effects on cardiac muscle, volume, function, things we are only beginning to understand. Europeans are already including SGLT2 inhibitors in their HF management, and the U.S. has to catch up.”
HFpEF: ‘Right now, we have nothing’
CV outcomes trials and meta-analyses demonstrated SGLT2 inhibitors address a triple goal of treatment for HF with reduced EF (HFrEF) — to live longer, stay out of the hospital and reduce debilitating symptoms while improving quality of life.
Whether the class of drugs can do the same for people with HFpEF, however, remains an open and intriguing question.
“The outcomes for people with HF with preserved ejection fraction are nearly as poor as those with HF with reduced ejection fraction,” Mikhail Kosiborod, MD, FACC, FAHA, vice president for research and Ben McCallister, MD, Endowed Chair in Cardiovascular Research at Saint Luke’s Mid America Heart Institute, and professor of medicine at the University of Missouri-Kansas City School of Medicine, told Endocrine Today. “Risk for death or hospitalization is very high, and quality of life is very poor. The pathophysiology of HFpEF is different than HFrEF, but the symptoms are frequently very similar.”
Two large trial programs are exploring the benefits of SGLT2 inhibitors in HFpEF. EMPEROR-Preserved is assessing the effects of empagliflozin related to CV death or hospitalization of adults with HFpEF. DELIVER is assessing the effect of dapagliflozin on reducing CV death or worsening HF of adults with HFpEF. Results from both trials are expected in the near future.
Two smaller trials offered a glimpse of the possible benefits in this population. Data from the SCORED and SOLOIST trials, presented at the AHA Scientific Sessions in November, showed that sotagliflozin (Lexicon), a novel dual SGLT1/SGLT2 inhibitor, reduced risk for CV death and hospitalization or urgent visits for HF compared with placebo. In SOLOIST, benefits were significant by about 1 month in an acute population; for the more chronic outpatient population in SCORED, benefit was still observed by 3 months, Bhatt said when presenting the data.
“What Dr. Bhatt showed at AHA was if you consider the totality of data from SCORED and SOLOIST in patients with HFpEF, it looks very favorable,” Kosiborod said. “Although it may not be definitive yet for SGLT2 inhibitors in HFpEF, these early results from well-designed randomized clinical trials of sotagliflozin are promising.”Open questions are a bit different for HFpEF, experts said. If there is a benefit with SGLT2 inhibitors, the question remains will benefit be driven predominantly by reductions in hospitalizations for HF, a reduction in CV death, or a combination of both. Also unanswered is the effects on symptom burden and quality of life.
“All of those are important questions, and it is too early to tell,” Kosiborod said. “It is extraordinarily difficult to reduce CV death in the HFpEF population, because it is so multifactorial. But even if we were to come out of these trials with the message that SGLT2 inhibitors show a meaningful reduction in hospitalizations — even without a reduction in mortality — it would still be incredibly important. HFpEF is now a majority of the people with HF, at least in the U.S. We have little to offer them today in terms of disease-modifying therapies. If we see that SGLT2 inhibitors provide a combination of benefits — reduction in hospitalizations and CV death — in HFpEF, that would be amazing, but we have to remember that, right now, we have almost nothing.”
Cross-specialty conversations
With multiple large trials now complete and more underway, evidence is compelling for HF benefits with SGLT2 inhibitors. The biggest challenge now is not just a need for additional data, but implementation science, Bhatt said.
“We need to make sure that patients who currently have guideline or labeled indications for SGLT2 inhibitors are actually getting them,” Bhatt said. “If they are not getting them, what are the barriers, economic or otherwise, that we need to overcome? These are drugs that have the potential to have a large impact on people with diabetes, and especially in diabetes plus either HF or chronic kidney disease. Barring contraindications, it is hard to see why they should not be on this type of medicine.”
To spread that message, cross-specialty collaboration and conversations are important, Subramanian said.
“In our area, there are maybe a handful of cardiologists who are comfortable starting these drugs. I call them the very brave cardiologists,” Subramanian said. “But cardiologists take care of so many different problems. There is counseling needed for these patients. If they are on other medications, those need to be adjusted. The successful cardiology groups that do this well have a pharmacist who handles the medication titration. Even though clinical research did not show an increase in urinary tract infection or Fournier’s gangrene, that is not real-world. There is real risk.”
Hesitancy to prescribe SGLT2 inhibitors remains an issue, either due to lack of comfort or understanding. Endocrinologists working together with cardiologists could help bridge that barrier, Subramanian said.
“In our setting, in an academic practice, it has been variable,” Subramanian said. “Very few cardiologists are comfortable. Often they will send a message through the electronic chart saying, ‘Hey, I’m interested in starting this patient on this drug, what do you think?’ It is a conversation, and dialogue is important.”
McGuire agreed.
“One of the things we must do as cardiologists is stop considering SGLT2 inhibitors ‘diabetes drugs,’” McGuire said. “As I have said since EMPA-REG OUTCOME, these are CV medications, with a side effect of glucose-lowering. We as cardiologists should become more and more comfortable prescribing them, completely independent of glucose considerations. That is an evolution that is occurring.”Click to enlarge
A new clinical care delivery model that prioritizes prevention and treatment of HF can help speed implementation of newer therapies, such as SGLT2 inhibitors, Kosiborod said.
“We built our own cardiometabolic center 2.5 years ago, and the results in terms of quality improvement were so compelling that we have started a national organization — the Cardiometabolic Center Alliance — helping other health care organizations build their own centers of excellence,” Kosiborod said. “I hope this process continues to accelerate. We just can’t wait for decades for efficacious therapies to be adopted in practice, especially for highly morbid conditions like heart failure.”
More to learn
As more trial data continue to reveal new chapters for the SGLT2 inhibitor story, researchers are anxious to learn what more the drugs could potentially do. In addition to trials assessing SGLT2 inhibitor effects for people with HFpEF, there are studies evaluating those hospitalized for HF, as well as patients with advanced chronic kidney disease with and without diabetes and patients post-MI who do not have diabetes.
“There are at least two, if not three studies using SGLT2 inhibitors looking at an early use, either in hospital or soon upon discharge,” Inzucchi said. “Why might that be helpful? Well, the benefit emerges rapidly.. Patients who are just discharged are vulnerable, and getting them potentially lifesaving therapy as soon as possible is probably important.”
Another study, DARE-19, evaluated the effect of dapagliflozin as a treatment for COVID-19 progression, complications and death among adults with CV, metabolic or renal risk factors. AstraZeneca announced in April that the trial did not meet its primary endpoints of organ dysfunction/all-cause death and change in clinical status. But the biggest lesson may be not to write off this drug class a treatment for a single condition, Kosiborod said.
“People like to compartmentalize drugs and interventions. We say drug A is for headache, drug B is for HF, drug C is for diabetes, drug D for kidney disease,” Kosiborod said. “What we see with SGLT2 inhibitors is just a wonderful demonstration of how this way of thinking is erroneous. We think we are done with SGLT2 inhibitors, and they have probably been one of the most extensively researched medications in the history of medicine. Yet, we are likely just scratching the surface.
“There are reasons to believe this class could have benefits through a variety of mechanisms in other disease states. Even in the cardiovascular field, after all these trials, there are many remaining questions,” Kosiborod said. “We should not repeat mistakes of the past.”
- References:
- American Heart Association. Diabetes and heart failure are linked; treatment should be too. June 6, 2019. Available at: www.heart.org/en/news/2019/06/06/diabetes-and-heart-failure-are-linked-treatment-should-be-too. Accessed April 7, 2021.
- Bhatt DL, et al. N Engl J Med. 2020;doi:10.1056/NEJMoa2030186.
- Bhatt DL, et al. N Engl J Med. 2020;doi:10.1056/NEJMoa2030183.
- Dunlay SM, et al. Circulation. 2019;doi:10.1161/CIR.0000000000000691.
- Kosiborod M. Circulation. 2021;doi:10.1161/CIRCULATIONAHA.120.052446.
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