A class of drugs originally designed to lower blood sugar in people with type 2 diabetes has crossed into entirely new territory — and the implications for heart failure patients, including those with no diabetes at all, are significant. Three SGLT2 inhibitors — dapagliflozin (Farxiga), empagliflozin (Jardiance), and sotagliflozin (Inpefa) — now carry FDA approval to treat heart failure regardless of whether the patient has diabetes. Dapagliflozin led the way with its initial approval on May 5, 2020, for heart failure with reduced ejection fraction, making it the first SGLT2 inhibitor cleared for this use in non-diabetic patients.
Empagliflozin followed in February 2022, and sotagliflozin joined them in May 2023. For the millions of Americans living with heart failure — a condition where the heart cannot pump blood efficiently enough to meet the body’s needs — this is not a minor regulatory footnote. These approvals were backed by landmark clinical trials involving tens of thousands of patients, and the results were striking enough that international guidelines now consider SGLT2 inhibitors one of the foundational treatments for heart failure. This article breaks down what these drugs are, how they work beyond glucose control, the clinical evidence behind each approval, who stands to benefit, what the risks look like, and why this matters for anyone concerned about cardiovascular and brain health.
Table of Contents
- Which Diabetes Drugs Are Now FDA-Approved for Heart Failure Without Diabetes?
- How Do Blood Sugar Drugs Help a Failing Heart?
- What Did the Clinical Trials Actually Show?
- What This Means for Patients Already on Heart Failure Medications
- Why This Matters for Brain Health and Dementia Risk
- Starting SGLT2 Inhibitors in the Hospital Setting
- Where the Evidence Is Heading
- Conclusion
- Frequently Asked Questions
Which Diabetes Drugs Are Now FDA-Approved for Heart Failure Without Diabetes?
Three drugs have crossed this threshold, each with a slightly different profile. Dapagliflozin (Farxiga), made by AstraZeneca, was first approved in May 2020 for heart failure with reduced ejection fraction — meaning patients whose hearts pump out 40% or less of the blood in the left ventricle with each beat. By May 2023, that approval expanded to cover a broader range of heart failure patients, including those with preserved ejection fraction. Empagliflozin (Jardiance), developed by Boehringer Ingelheim and Eli Lilly, received FDA approval in February 2022 and became the first drug approved across the full spectrum of heart failure — reduced, mid-range, and preserved ejection fraction — regardless of diabetes status.
Sotagliflozin (Inpefa), from Lexicon Pharmaceuticals, earned its approval on May 26, 2023, as the first dual SGLT1/SGLT2 inhibitor for heart failure, also covering the full range of ejection fractions. The distinction between these three matters. Dapagliflozin and empagliflozin are pure SGLT2 inhibitors, while sotagliflozin blocks both SGLT1 and SGLT2 receptors, which may offer additional benefits in the gut related to glucose absorption and GLP-1 release. In practice, cardiologists now have multiple options to choose from depending on the patient’s specific heart failure subtype, tolerance profile, and insurance coverage. What they share in common is the remarkable finding that their cardiac benefits do not depend on lowering blood sugar — something that took the cardiology world by surprise when the first trial results came in.
How Do Blood Sugar Drugs Help a Failing Heart?
This is the question that puzzled researchers for years, and the honest answer is that the mechanism is still not fully understood. SGLT2 inhibitors work in the kidneys by blocking the reabsorption of glucose and sodium, which means they promote the excretion of both sugar and salt in the urine. The sodium loss produces a mild diuretic effect — reducing fluid overload, which is a constant threat in heart failure. But this alone does not explain the magnitude of the benefits seen in trials, and several additional mechanisms are under investigation: reduced inflammation, improved cardiac energy metabolism (the heart may shift to using more efficient fuel sources like ketone bodies), decreased cardiac fibrosis, and protection against oxidative stress. However, it would be a mistake to assume these drugs are a replacement for established heart failure medications.
They are not. The current understanding treats SGLT2 inhibitors as an addition to the existing regimen, not a substitute. A patient with heart failure who stops their beta-blocker or ACE inhibitor because they started an SGLT2 inhibitor would be making a dangerous trade. These drugs work best as part of a combination strategy, and their benefits in trials were observed on top of standard background therapy. If you or a loved one has heart failure and no diabetes, the conversation with a cardiologist should be about adding this drug class, not swapping it in.
What Did the Clinical Trials Actually Show?
The evidence behind these approvals is unusually strong by pharmaceutical standards. The DAPA-HF trial, which supported dapagliflozin’s initial approval, enrolled 4,744 patients with heart failure and reduced ejection fraction. Over a median follow-up of 18.2 months, dapagliflozin reduced the composite risk of cardiovascular death or worsening heart failure by 26% compared to placebo, with event rates of 11.6 versus 15.6 per 100 patient-years (P < 0.0001). In concrete terms, the number needed to treat was 21 — meaning for every 21 patients treated, one cardiovascular death or hospitalization was prevented. That is a meaningful number in cardiology, where many interventions require treating 50 or 100 patients to prevent a single event. Crucially, the benefits were consistent regardless of whether patients had diabetes. Empagliflozin's path was equally compelling but broader.
The EMPEROR-Reduced trial confirmed benefits in patients with reduced ejection fraction, while the EMPEROR-Preserved trial broke new ground as the first successful trial showing benefit in heart failure with preserved ejection fraction — a subtype that had resisted nearly every drug ever tested against it. For decades, HFpEF was sometimes called the “graveyard of clinical trials” because nothing seemed to work. Empagliflozin changed that. Sotagliflozin brought its own evidence through two Phase 3 trials — SOLOIST-WHF and SCORED — enrolling nearly 12,000 patients combined. The SOLOIST-WHF trial, which focused on patients recently hospitalized for worsening heart failure, showed a 33% reduction in the composite endpoint compared to placebo. These are not marginal findings. They represent a genuine shift in how heart failure is treated.
What This Means for Patients Already on Heart Failure Medications
The practical question for patients and families is straightforward: should someone with heart failure who does not have diabetes be on one of these drugs? According to current guidelines, quite possibly yes. The 2023 European Society of Cardiology guidelines gave SGLT2 inhibitors a Class I, Level A recommendation for heart failure with preserved and mid-range ejection fraction — the strongest possible endorsement, based on the highest quality of evidence. SGLT2 inhibitors are now considered one of the “four pillars” of treatment for heart failure with reduced ejection fraction, alongside beta-blockers, mineralocorticoid receptor antagonists, and ACE inhibitors or ARNIs (like sacubitril/valsartan). The tradeoff to consider is practical, not just clinical.
Adding another medication means another pill, another co-pay, and another set of potential side effects to monitor. SGLT2 inhibitors can cause urinary tract infections, genital fungal infections (particularly in women), and in some cases dehydration or low blood pressure, especially in patients already taking diuretics. The risk of diabetic ketoacidosis is primarily a concern in patients with diabetes, but it has been reported rarely in non-diabetic patients. For many people, the demonstrated 26–33% reductions in cardiovascular death and hospitalization will clearly outweigh these risks. But the decision should be individualized — a frail elderly patient on six other medications faces a different calculation than a relatively robust 60-year-old with new-onset heart failure.
Why This Matters for Brain Health and Dementia Risk
For readers of a brain health and dementia care website, the connection between heart failure drugs and cognitive health is not a stretch — it is physiologically direct. Heart failure reduces blood flow to the brain, and chronic cerebral hypoperfusion is a well-established risk factor for vascular dementia and may accelerate Alzheimer’s disease pathology. Studies have shown that people with heart failure have roughly double the risk of developing dementia compared to the general population. Any intervention that improves cardiac output and reduces heart failure hospitalizations has the potential — at least in theory — to protect brain health downstream. There is a limitation here that deserves honest acknowledgment.
No SGLT2 inhibitor trial has yet been designed or powered to measure cognitive outcomes as a primary endpoint. The brain health argument remains plausible but not yet proven by dedicated research. Emerging observational data and secondary analyses from existing trials are beginning to hint at neuroprotective effects, including reduced neuroinflammation and improved cerebral blood flow, but these are early signals rather than established facts. Families managing a loved one’s dementia alongside heart failure should discuss these drugs with the care team, but should not expect them to be a dementia treatment per se. The value here is in treating the heart failure effectively, which removes one of the significant contributors to cognitive decline.
Starting SGLT2 Inhibitors in the Hospital Setting
One of the more recent developments is the growing support for initiating SGLT2 inhibitors during a hospital stay for acute heart failure, rather than waiting until the patient has been stabilized and discharged. The logic is straightforward: patients hospitalized for heart failure decompensation are at extremely high risk for rehospitalization within 30 to 90 days, and the SOLOIST-WHF trial specifically studied sotagliflozin in this population — patients randomized before or shortly after discharge — and found the 33% reduction in adverse outcomes. Recent evidence and updated guidelines now support in-hospital initiation as both safe and beneficial, giving clinicians a narrow but important window to intervene.
This is especially relevant for caregivers navigating a loved one’s hospital discharge. If a heart failure patient leaves the hospital without a discussion about SGLT2 inhibitors, it is reasonable to ask the cardiologist whether one of these drugs should be added to the regimen. The data supports doing so.
Where the Evidence Is Heading
The broader numbers tell a compelling story about the population-level impact of these drugs. Mortality rates in heart failure patients treated with SGLT2 inhibitors have been observed to decrease from 8.5 to 5.8 per 100 person-years, and hospitalizations have been reduced by up to 30% in non-diabetic heart failure patients. These are not small margins. As the medical community accumulates more real-world data beyond controlled trials, the picture is likely to become even clearer about which patients benefit most and whether the cognitive protection hypothesis holds up under rigorous testing.
The pace of research here is rapid. New trials are exploring SGLT2 inhibitors in acute myocardial infarction, chronic kidney disease with cardiac complications, and — of particular interest for this audience — their potential role in neurodegenerative disease prevention. The reclassification of these drugs from “diabetes medications” to “cardiovascular medications that also treat diabetes” represents one of the more significant therapeutic shifts in modern cardiology. For patients and families dealing with the intersection of heart failure and cognitive decline, these are drugs worth knowing about and worth discussing at the next appointment.
Conclusion
Three SGLT2 inhibitors — dapagliflozin, empagliflozin, and sotagliflozin — are now FDA-approved to treat heart failure in patients who do not have diabetes, backed by large clinical trials showing reductions of 26% to 33% in cardiovascular death and heart failure hospitalizations. International guidelines have elevated these drugs to first-line status, designating them as one of the four pillars of heart failure therapy. The benefits are consistent across the spectrum of heart failure types, including preserved ejection fraction, where almost nothing else has worked.
For anyone managing heart failure alongside concerns about cognitive decline, effective cardiac treatment is brain protection by another name. While SGLT2 inhibitors have not been proven to prevent dementia directly, their ability to improve heart function and reduce hospitalizations addresses one of the major modifiable risk factors for vascular cognitive impairment. If you or someone you care for has heart failure — with or without diabetes — ask the treating cardiologist whether an SGLT2 inhibitor belongs in the medication plan. The evidence supporting these drugs is strong, the guidelines are clear, and the window to benefit is open.
Frequently Asked Questions
Can I take an SGLT2 inhibitor for heart failure if I do not have diabetes?
Yes. Dapagliflozin, empagliflozin, and sotagliflozin are all FDA-approved for heart failure regardless of diabetes status. The clinical trials specifically included non-diabetic patients and found consistent benefits in both groups.
Will an SGLT2 inhibitor lower my blood sugar dangerously if I am not diabetic?
In patients without diabetes, SGLT2 inhibitors do not typically cause clinically significant drops in blood sugar. The risk of hypoglycemia is very low in non-diabetic patients because the body’s other glucose-regulation mechanisms remain intact.
Which SGLT2 inhibitor is best for heart failure?
There is no head-to-head trial comparing the three approved drugs against each other. The choice often depends on the specific type of heart failure, the patient’s other medications, insurance coverage, and side effect profile. All three have strong evidence supporting their use.
Can these drugs help prevent dementia?
This has not been proven. Heart failure is a known risk factor for dementia, and treating heart failure effectively may reduce that risk. Some early research suggests SGLT2 inhibitors may have neuroprotective effects, but dedicated cognitive outcome trials have not yet been completed.
What are the most common side effects?
Urinary tract infections, genital yeast infections, increased urination, and in some cases low blood pressure or dehydration. These are generally manageable but should be monitored, especially in elderly patients or those already on diuretics.
Should an SGLT2 inhibitor be started in the hospital during a heart failure admission?
Recent evidence supports in-hospital initiation, particularly based on the SOLOIST-WHF trial with sotagliflozin. Guidelines increasingly favor starting these drugs before discharge rather than waiting for an outpatient follow-up, given the high risk of rehospitalization in the weeks after discharge.
