Heart failure and diabetes are closely intertwined. Diabetes affects not only coronary artery blood flow, but also the myocardium. Patients with type 2 diabetes are at risk of heart failure due to intrinsic myocardial disease, resulting in increased myocardial hypertrophy, fibrosis and stiffness. This can also lead to a form of heart failure described in literature as diabetic cardiomyopathy.
“Because diabetes and heart failure intersect at many different levels, it is critical to think aBecause diabetes and heart failure intersect at many different levels, it is critical to think about diabetes as not only a disease of the pipes but also a disease of the pump itself. We need to start thinking about how we are managing patients with diabetes, with particular emphasis on those with established cardiovascular disease,” says Timothy Gong, MD, FACC, advanced heart failure cardiologist on the medical staff at Baylor University Medical Center, part of Baylor Scott & White Health. “Studies have shown that SGLT2 inhibitors reduce heart failure hospitalizations and cardiovascular death in patients with established heart failure and reduced ejection fraction. SGLT2 inhibitors are now included in the 2021 Expert Opinion Consensus Decision Pathway from the American College of Cardiology.”
SGLT2 is expressed in the proximal renal tubules, which are responsible for the majority of filtered glucose reabsorption from the tubular lumen. SGLT2 inhibitors reduce reabsorption of filtered glucose, lower the renal threshold for glucose, thereby increasing urinary glucose excretion. SGLT2 inhibitors also reduce sodium reabsorption and increase the delivery of sodium to the distal tubule. This natriuresis leads to decreased intraglomerular pressure and proteinuria. By increasing glucose and sodium excretion, SGLT2 inhibitors can lower blood pressure, improve arterial stiffness, decrease weight, and improve A1C.
“While the exact mechanism of SGLT2 inhibitors is not yet entirely understood, I believe the outcomes from recent large-scale clinical trials demonstrate this is not just a glucose uric effect,” says Dr. Gong. “This is attacking heart failure from multiple different facets, which should make us think about the other drugs we use, such as beta blockers, ARNIs, ACE inhibitors and MRAs.”
Clear clinical trial data
The results of two particular clinical trials likely contributed to SGLT2 inhibitors being included in the ACC Expert Consensus Decision Pathway. The DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial looked at the efficacy and safety of dapagliflozin, an SGLT2 inhibitor, in more than 4,700 patients with heart failure and reduced ejection fraction, whether or not the patients had diabetes. Among these patients, the risk of worsening heart failure or death from cardiovascular causes was lower among those who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes.
“Even prior to three months, there is a statistically significant distinction between placebo and dapagliflozin. This is very important because we often like to pin some of the benefits of these heart failure therapies just on the fact that they improve hospitalization for heart failure, but this trial is showing it is not just improving heart failure hospitalizations, it is also improving death from cardiovascular causes. Even for patients who are not diabetic, it is still the favored treatment.”
Another major trial – EMPEROR-Reduced – was designed to evaluate the safety and efficacy of empagliflozin, another SGLT2 inhibitor, versus placebo on top of guideline-directed medical therapy (GDMT) in more than 3,700 patients with a diagnosis of heart failure and HFrEF. The primary endpoint was the time to first event of cardiovascular death or hospitalization for worsening heart failure. The results were similar to DAPA-HF. Among patients who were receiving recommended therapy for heart failure, those in the empagliflozin group had a lower risk of the composite of cardiovascular death and heart failure hospitalization than those in the placebo group, whether they had diabetes or not.
“The difference in results in the two groups shows up earlier than three months and the treatment effect persists for well over a year,” Dr. Gong says. “For first and recurrent hospitalizations for heart failure, the treatment effect is pronounced at three years.”
ACC Expert Opinion Guidelines
The 2021 update to the 2017 Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment includes recommendations for the use of SGLT2 inhibitors. These recommendations state these medications should be administered in conjunction with GDMT for heart failure.
For a patient with HFrEF (EF < 40%) with or without diabetes and NYHA Class II-IV heart failure, he or she should be placed on an angiotensin-converting enzyme (ACE) inhibitor, angiotensin receptor-neprilysin inhibitor (ARNI), an angiotensin receptor blocker (ARB) and an evidence-based beta blocker. Clinicians then seem to have the choice of an aldosterone antagonist, such as spironolactone, an SGLT2 inhibitor, and vasodilators, such as hydralazine and isosorbide. The recommendation seems to be less strong for an HCN channel blocker like ivabradine. Consistent with what was found in both the DAPA-HF and EMPEROR-Reduced trials, the dosage for either dapagliflozin and empagliflozin is 10 mg for each.
A new algorithm for GDMT
“Low doses of heart failure therapies still have a reduction in morbidity and mortality. The magnitude of the treatment benefit for each drug class is independent of that produced by the other agents,” Dr. Gong says. “For example, an MRA does not modify the efficacy of an ARNI, and the use of an ARNI does not necessarily influence the efficacy of an SGLT2 inhibitor.
“When you look at the conventional sequencing of medications that is recommended by the guidelines, the process could take six months,” Dr. Gong continues. “That’s why it is so important to remember that there was significant benefit in the SGLT2 inhibitor trials prior to three months with regard to cardiovascular death and hospitalizations for heart failure. That’s really key to thinking about a change in how we initiate these drugs.”
A novel algorithm for GDMT was published in Circulation, Dec. 30, 2020. In the publication, the authors propose starting with a guideline-directed beta blocker followed by an SGLT2 inhibitor. Then, when the patient potentially has more blood pressure room, an ARNI can be prescribed followed by a mineralcorticoid receptor antagonist, all within a short period of time. The guidelines recommend a time limit of two weeks for initiating each of these changes.
Significant benefits outweigh low percentage risks
As with many medications, clinicians must weigh the benefits versus any potential risks. SGLT2 inhibitors have a low risk of genital infections and diabetic ketoacidosis, but the risk of amputations was not found in any of the later trials of SGLT2 inhibitors. They may increase the risk of volume depletion, but no significant increased risk of acute kidney failure has been reported. This often can be addressed by decreasing the dose of the loop diuretic to accommodate the SGLT2 inhibitor. Overall, the evidence clearly shows there are benefits that outweigh those low percentage risks.
The favorable effects of SGLT2 inhibitors include prevention of incidence and treatment of established heart failure; reduction of major cardiovascular events; reduction of blood pressure and weight; preservation of renal function; and improvement in glycemic control.
“I think this should shake some of the foundations of our management of diabetes,” Dr. Gong says. “Should metformin still be the first line drug of choice for diabetes? While there are still questions to be answered, we know SGLT2 inhibitors reduce inflammation, oxidative stress, fibrosis, intra-glomerular hypertension and sympathetic nervous system activation. They may improve mitochondrial function and myocardial efficiency, which may be reason they have such profound effect in patients with cardiovascular disease. Clinical trial data show that SGLT2 inhibitors should be an important part of the armamentarium for treating heart failure with reduced ejection fraction.”