SGLT2 Inhibitors in Patients Without Diabetes: When and Why We Use Them

A 71-year-old woman comes back to clinic three weeks after starting a new medication called empagliflozin. She's puzzled. Her blood sugar has always been normal. Her A1c last month was 5.4. She has heart failure with a preserved ejection fraction, some mild kidney disease, and well-controlled hypertension. Her question, asked politely but with a touch of confusion, is the same one I hear several times a week. "Why did you put me on a diabetes drug? I don't have diabetes." Her pharmacist asked the same thing. Her son, who looked the medication up online, called to make sure I hadn't made a mistake. I hadn't. The medication is one of the more meaningful additions to her treatment plan in years, and it has very little to do with diabetes anymore.

I'm Dr. Damian Rasch, a cardiologist in Encinitas. SGLT2 inhibitors are medications originally developed and approved as glucose-lowering drugs for type 2 diabetes. The class includes empagliflozin (Jardiance), dapagliflozin (Farxiga), canagliflozin (Invokana), and ertugliflozin (Steglatro). Over the past decade, large clinical trials have shown that these drugs reduce hospitalizations for heart failure, slow the progression of chronic kidney disease, and reduce cardiovascular death, in many cases independent of whether the patient has diabetes at all. They've quietly become one of the more effective tools we have in cardiology and nephrology, and the diabetes label has aged into something of a misnomer. This article walks through the story of how that happened, how these drugs work in the body, what the trials showed in patients without diabetes, who should consider starting one, what side effects to watch for, and how to think about cost and access.

How a Diabetes Drug Stopped Being Just a Diabetes Drug

The story starts in 2008, when the FDA changed the rules for how new diabetes drugs got approved. After concerns about cardiovascular safety with rosiglitazone, the agency required all new diabetes drugs to undergo large cardiovascular outcome trials to prove they didn't increase the risk of heart attacks, strokes, or cardiovascular death. The intent was defensive. Drug companies were being asked to demonstrate safety, not benefit. The expectation across the field was that these trials would show neutral cardiovascular outcomes and the drugs would proceed to market on the basis of their glucose-lowering effects.

Then in 2015, the EMPA-REG OUTCOME trial published its results. The trial enrolled patients with type 2 diabetes who already had established cardiovascular disease and randomized them to empagliflozin or placebo on top of standard care. The expected result was non-inferiority for the cardiovascular safety endpoint. The actual result was startling. Empagliflozin reduced cardiovascular death by 38 percent, all-cause mortality by 32 percent, and hospitalization for heart failure by 35 percent. These were not subtle effects. The cardiology and diabetes communities were caught off guard, and a flurry of follow-up trials began testing whether other drugs in the class produced similar effects and whether the benefits extended beyond patients with diabetes.

What emerged over the next several years was a redefinition of what these drugs were for. The cardiovascular and renal benefits turned out to be largely independent of the glucose-lowering effects, the patient's starting blood sugar, or whether the patient had diabetes at all. By 2020, dedicated heart failure trials and dedicated kidney disease trials began enrolling patients regardless of diabetes status, and the results kept landing in the same direction. SGLT2 inhibitors are now standard of care for heart failure with reduced ejection fraction, heart failure with preserved ejection fraction, and chronic kidney disease with proteinuria, in many cases regardless of diabetes status. The diabetes label is still on the bottle. The reason for prescribing them often has nothing to do with diabetes.

How SGLT2 Inhibitors Actually Work

The name describes the original mechanism. SGLT2 stands for sodium-glucose cotransporter 2, a protein in the proximal tubule of the kidney that reabsorbs filtered glucose back into the bloodstream. Under normal conditions, the kidneys filter about 180 grams of glucose per day and reabsorb almost all of it. SGLT2 does about 90 percent of that reabsorption. Block it with a medication, and a large amount of glucose spills into the urine. In a patient with elevated blood sugar, this lowers the blood sugar. In a patient with normal blood sugar, the body compensates by reducing glucose excretion at lower thresholds, and blood sugar tends to stay roughly the same.

The cardiovascular and renal benefits, though, don't track with the glucose-lowering effect. They show up in patients without diabetes and in patients whose blood sugar barely changes on the medication. The mechanisms are still being worked out, but several lines of evidence point to a few simultaneous effects in the heart and kidneys.

The first is natriuresis. SGLT2 doesn't only transport glucose; it co-transports sodium. Blocking it causes the kidney to excrete more sodium along with the glucose, which produces a mild diuretic effect. The diuresis is gentler than what loop diuretics produce and tends to remove fluid from the interstitial space (the tissue compartments) more than from the intravascular space (the blood vessels). For a patient with heart failure who has chronic congestion, this is exactly the kind of fluid offloading that matters. It reduces preload on the heart and reduces afterload through blood pressure effects without producing the same volume contraction and neurohormonal activation that aggressive loop diuretic dosing does.

The second mechanism is hemodynamic. SGLT2 inhibitors restore tubuloglomerular feedback by changing the sodium delivery to the macula densa, which causes constriction of the afferent arteriole of the glomerulus and a small reduction in intraglomerular pressure. The effect lowers the GFR by a few points in the first weeks of therapy (this is the classic early dip in creatinine that we see and don't worry about), and over the long term it slows the progression of kidney disease. Less glomerular hyperfiltration means less damage to the filtering apparatus over years.

The third mechanism is metabolic. SGLT2 inhibitors shift fuel utilization in the heart. With a small amount of glucose continuously spilling into the urine, the body increases ketone production at modest levels. The failing heart appears to use ketones more efficiently than it uses fatty acids or glucose, and providing this alternative fuel source seems to improve myocardial energetics. The effect is subtle but appears to contribute to the heart failure benefits.

There are likely additional effects on inflammation, oxidative stress, sympathetic nervous system tone, and erythropoietin release (most patients see a small bump in hematocrit on these drugs, which may itself contribute to outcomes). The story is still being written, but the bottom line for patients is that these medications work through several pathways that converge on better cardiovascular and renal outcomes, and most of those pathways have nothing to do with blood sugar.

Heart Failure With Reduced Ejection Fraction

The DAPA-HF trial, published in 2019, was the first dedicated heart failure trial of an SGLT2 inhibitor. It enrolled almost 5,000 patients with heart failure and an ejection fraction of 40 percent or less, regardless of whether they had diabetes. About 55 percent of the patients did not have diabetes. They were randomized to dapagliflozin or placebo on top of guideline-directed medical therapy (which already included beta blockers, ACE inhibitors or ARNIs, and mineralocorticoid receptor antagonists in most patients).

The results were clear. Dapagliflozin reduced the composite of cardiovascular death or worsening heart failure by 26 percent. The benefit was the same in patients with diabetes and in patients without diabetes. All-cause mortality dropped by 17 percent. The number needed to treat to prevent one bad outcome was about 21 patients over a median follow-up of just over a year. For a heart failure trial, those numbers were exceptional, and the benefit was layered on top of every other proven heart failure therapy.

EMPEROR-Reduced, published a year later, did the same thing with empagliflozin and produced similar results. About half the patients didn't have diabetes. The composite primary endpoint dropped by 25 percent. Hospitalization for heart failure dropped substantially. The renal endpoints improved as well. Two large trials with two different drugs in the class converged on the same answer, and the heart failure guidelines updated quickly.

The 2022 AHA/ACC/HFSA guideline recommends an SGLT2 inhibitor as one of the four foundational pillars of HFrEF therapy, alongside ARNIs (or ACE inhibitors), beta blockers, and mineralocorticoid receptor antagonists. The recommendation does not require diabetes. For a patient with HFrEF, the medication is appropriate regardless of glucose status.

Heart Failure With Preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF) was, until recently, one of the more frustrating diagnoses in cardiology. The condition affects roughly half of all heart failure patients, often in older women with hypertension, obesity, atrial fibrillation, and chronic kidney disease, and for decades we had no medications that clearly improved outcomes. Renin-angiotensin system blockers, beta blockers, and mineralocorticoid antagonists each had small or equivocal benefits. Patients felt symptomatic and we had limited tools.

EMPEROR-Preserved, published in 2021, changed that. The trial enrolled almost 6,000 patients with heart failure and an ejection fraction above 40 percent, regardless of diabetes. Empagliflozin reduced the composite of cardiovascular death or hospitalization for heart failure by 21 percent. Hospitalization rates dropped substantially. Cardiovascular mortality didn't reach statistical significance on its own, but the heart failure event reduction was clear and clinically meaningful. The benefit applied across ejection fraction strata up to about 60 to 65 percent, with attenuation at the highest ejection fractions.

DELIVER, published in 2022, tested dapagliflozin in a similar population and produced confirmatory results. The composite of worsening heart failure or cardiovascular death dropped by 18 percent. The benefit was consistent across ejection fraction subgroups, including patients with mildly reduced ejection fraction (the so-called HFmrEF range from 41 to 49 percent), and including patients without diabetes.

Together, these two trials gave HFpEF its first class of medications with clear evidence of benefit. For a patient with HFpEF, an SGLT2 inhibitor is now the first-line disease-modifying therapy. We still treat the comorbidities (hypertension, atrial fibrillation, sleep apnea, obesity, deconditioning), but we add an SGLT2 inhibitor early in most cases. Diabetes is not required.

Chronic Kidney Disease

The kidney trials extended the story further. DAPA-CKD, published in 2020, enrolled patients with chronic kidney disease (eGFR 25 to 75) and proteinuria, with or without diabetes. Roughly a third of the patients did not have diabetes. The composite renal endpoint (sustained decline in eGFR, end-stage kidney disease, or death from renal or cardiovascular causes) dropped by 39 percent on dapagliflozin. All-cause mortality dropped by 31 percent. The trial was stopped early because of overwhelming benefit.

EMPA-KIDNEY, published in 2022, broadened the population further. It enrolled patients with CKD across a wider range of GFRs and didn't require proteinuria for many of the participants. Most of the enrolled patients did not have diabetes. Empagliflozin reduced the composite of kidney disease progression or cardiovascular death by 28 percent. The benefit was consistent across the full range of GFRs studied, including patients with eGFRs as low as 20.

For patients with CKD and proteinuria, SGLT2 inhibitors are now part of standard care alongside ACE inhibitors or ARBs. The KDIGO guideline recommends SGLT2 inhibitors for patients with CKD and an eGFR of at least 20, with or without diabetes. The trials extended the floor of who benefits, and the older notion that these drugs only worked in patients with relatively preserved kidney function has been revised downward.

Who Should Consider an SGLT2 Inhibitor Without Diabetes

In my practice, the patients I'm most likely to start on an SGLT2 inhibitor in the absence of diabetes fall into a few broad categories.

Patients with heart failure with reduced ejection fraction (an EF of 40 percent or less) are the clearest case. Unless there's a contraindication, every patient with HFrEF should be on one of these medications. The benefit is substantial, the evidence is clean, and the medication usually fits well alongside the other heart failure drugs. I generally start dapagliflozin 10 mg daily or empagliflozin 10 mg daily.

Patients with heart failure with preserved ejection fraction are the next group. The benefit is somewhat smaller in absolute terms than in HFrEF, but it's the best evidence-based therapy we have for HFpEF. For a symptomatic HFpEF patient with hospitalization risk, I almost always recommend starting one.

Patients with chronic kidney disease, especially with significant proteinuria, are the third group. The kidney protection appears to be largely independent of diabetes, and a patient with proteinuric CKD on a maximal ACE inhibitor or ARB usually has more to gain from adding an SGLT2 inhibitor than from any other intervention available outside of dialysis prevention.

There are also overlap patients. Someone with mildly reduced ejection fraction, mild CKD, and recurrent heart failure admissions has multiple reasons to be on the medication. The trials didn't require purity of indication. A patient with HFpEF and CKD gets the cardiovascular benefit, the renal benefit, and a small reduction in blood pressure as a bonus.

Patients without any of these conditions but with established cardiovascular disease are a more nuanced case. The original EMPA-REG and CANVAS trials showed cardiovascular benefit in patients with diabetes and established cardiovascular disease, but the equivalent trial in non-diabetic patients with cardiovascular disease alone hasn't been done. I don't routinely start SGLT2 inhibitors in patients with stable coronary artery disease who don't have heart failure or kidney disease, even if they have multiple cardiovascular risk factors.

Side Effects and What to Watch For

SGLT2 inhibitors are generally well tolerated, but there are a handful of side effects worth knowing about.

Genitourinary infections are the most common. Because the drugs increase glucose in the urine, the genital area becomes more hospitable to yeast and certain bacteria. Genital mycotic infections (yeast infections in women, balanitis in men) occur in about 5 to 10 percent of patients on these drugs. They're usually mild and respond to standard antifungal treatment. Urinary tract infections occur slightly more often as well, though the increase is modest. Good genital hygiene, especially in the first few weeks of therapy, lowers the risk meaningfully.

Volume depletion can occur in the first few weeks of therapy, especially in elderly patients on loop diuretics. The mechanism is the natriuretic effect that does so much good in heart failure. In someone who is already dry on a high dose of furosemide, adding an SGLT2 inhibitor can tip them into orthostasis or pre-syncope. The fix is usually a small reduction in the loop diuretic dose at the time of initiation. I often drop the diuretic by 25 to 50 percent for the first two to three weeks and then re-titrate based on weight, blood pressure, and symptoms.

Euglycemic diabetic ketoacidosis is a rare but serious complication that's worth understanding. The mechanism involves a shift toward ketone production combined with relative insulin deficiency. Risk factors include prolonged fasting, very low carbohydrate diets, severe acute illness, recent surgery, alcohol binges, and any state that combines reduced caloric intake with physiologic stress. The risk in patients without diabetes appears very low (much lower than in patients with type 1 or insulin-dependent type 2 diabetes), but it's not zero. The classic teaching is that any patient on an SGLT2 inhibitor who develops nausea, vomiting, abdominal pain, or air hunger needs to have ketones checked, even if their blood sugar is normal. The presentation can mimic a benign GI illness.

Sick day rules apply. If a patient on an SGLT2 inhibitor develops a serious illness with vomiting, an inability to eat, or dehydration, the medication should be held until they recover. The same rule applies before major surgery; most guidelines recommend stopping the medication three to four days before a planned surgery and resuming once the patient is eating, drinking, and clinically stable.

Necrotizing fasciitis of the perineum (Fournier's gangrene) was flagged by the FDA as a rare adverse event with these drugs. The signal is real but rare; the absolute incidence in trials and post-marketing surveillance is very low. Patients should be told to seek urgent care for severe pain, swelling, or redness in the genital or perineal area, especially with fever.

Lower-extremity amputation was a signal seen with canagliflozin in the CANVAS program but has not been replicated with the other SGLT2 inhibitors and is not seen in the heart failure or CKD trials. I rarely use canagliflozin in patients with peripheral arterial disease, but the concern doesn't extend to dapagliflozin or empagliflozin in the same way.

A small early dip in eGFR is expected and is not a reason to stop the medication. The creatinine often rises by a few points in the first few weeks and then stabilizes. Long-term GFR decline is slower on the medication than off it. We tell patients about the expected dip in advance so the lab result doesn't trigger panic at the first follow-up visit.

Cost and Access

The honest answer about cost is that these drugs remain expensive. Brand-name dapagliflozin and empagliflozin run several hundred dollars a month in cash price, and even with insurance, copays can be steep. Manufacturer coupons are available for many patients with commercial insurance and can bring the copay down meaningfully. For Medicare patients, the negotiated prices under the Inflation Reduction Act took effect for some of these drugs in 2026 and have lowered out-of-pocket costs, though the details depend on the specific plan and benefit phase.

Generic dapagliflozin is on the horizon. Patent expirations and biosimilar timelines should bring generic versions to the US market in the next several years. When that happens, the access conversation will look different, and we'll likely see broader use across populations who are currently priced out.

In the meantime, the patient assistance programs through the manufacturers are worth knowing about. Both dapagliflozin and empagliflozin have programs for patients without insurance or with high copays. The eligibility criteria are income-based, and the programs can provide the medication at no or low cost for patients who qualify. My office helps patients apply when cost is the barrier, and the success rate on those applications is reasonable.

When cost is prohibitive, the conversation about whether the medication is worth pursuing is real. For a patient with HFrEF and recent hospitalizations, the math usually favors finding a way to get the medication. For a patient with stable HFpEF and mild symptoms, the cost-benefit analysis is more individual.

Common Patient Questions

If I don't have diabetes, will this drug make my blood sugar drop too low?

No. SGLT2 inhibitors don't cause hypoglycemia in patients without diabetes. The mechanism is glucose excretion in the urine, and the kidneys auto-regulate that excretion based on blood glucose levels. Below a certain threshold, glucose stops spilling, and blood sugar stays in the normal range. Patients without diabetes who take these medications have blood sugars that look the same on the medication as off it.

Will I gain weight or lose weight?

Most patients lose a small amount of weight, typically two to five pounds over several months. The weight loss comes from a combination of glucose excretion (each gram of glucose is four calories, and several dozen grams a day excreted adds up) and a mild diuretic effect. The weight loss is modest and is not the reason to use the medication, but it's a welcome side effect for many patients.

Why does my creatinine go up after starting it?

The early rise in creatinine is expected and not a sign of harm. The medication causes the small artery feeding the kidney's filtering unit to constrict slightly, which reduces the pressure inside the filter and lowers the GFR by a few points. Over the long term, the lower pressure protects the kidney and slows decline in function. We expect the creatinine to bump up in the first few weeks and then stabilize. We don't stop the medication for this finding.

Should I stop the medication if I get sick?

Yes, in some situations. If you develop a significant illness with vomiting, dehydration, or an inability to eat, hold the medication until you've recovered. The same applies before surgery, where most guidelines recommend stopping three to four days in advance. The reason is to reduce the risk of euglycemic ketoacidosis during physiologic stress. Resume the medication once you're back to your baseline.

Do I need to monitor my blood sugar?

Routine glucose monitoring isn't needed for patients without diabetes. We do typically recheck basic labs (creatinine, electrolytes) a few weeks after starting, and again at the next routine visit. If symptoms suggest possible euglycemic ketoacidosis, that's a different conversation, and we'd check ketones in addition to glucose.

How long do I need to take it?

The current evidence supports indefinite use. The trials showed continuing benefit over years of follow-up, and stopping the medication appears to reverse some of the gains. For a patient with HFrEF, HFpEF, or CKD, this is a long-term medication, similar in that respect to a beta blocker or an ACE inhibitor.

Can I take it with my other heart medications?

Yes. SGLT2 inhibitors layer on top of beta blockers, ACE inhibitors, ARBs, ARNIs, mineralocorticoid receptor antagonists, and diuretics without major interactions. The trials tested SGLT2 inhibitors as add-on therapy to existing guideline-directed medical therapy, and the benefit was preserved. The one practical adjustment is sometimes a reduction in loop diuretic dose at initiation to avoid over-diuresis.

Is one drug in the class better than another?

For practical purposes, dapagliflozin and empagliflozin are interchangeable in cardiology and nephrology. The trials don't show meaningful differences between them in heart failure or CKD outcomes. Canagliflozin has the older amputation signal that we generally avoid in patients with peripheral arterial disease. Ertugliflozin has weaker cardiovascular outcome data. The choice between dapagliflozin and empagliflozin often comes down to insurance formulary, cost, and what the patient can access.

When to Escalate Care

Call 911 or go to the emergency department for severe abdominal pain, persistent vomiting, rapid breathing, confusion, or air hunger while on an SGLT2 inhibitor. These can signal euglycemic diabetic ketoacidosis, which is rare but treatable when caught early. The presentation can look like a stomach virus, and the standard glucose check can be reassuring even when ketones are dangerously high. If you can mention to the team that you're on an SGLT2 inhibitor, that prompts the right workup.

Seek urgent evaluation for severe genital or perineal pain, swelling, or redness with fever. The risk of necrotizing infection in this area is low but real, and early treatment makes the difference between a manageable problem and a catastrophic one.

Contact your cardiologist or primary care office for new lightheadedness or near-fainting after starting the medication, especially in the first few weeks. This usually means a small loop diuretic adjustment is needed, and we'd rather make that adjustment in clinic than have you stop the medication entirely.

Schedule a clinic visit within four to six weeks of starting the medication for routine follow-up. We recheck labs, review tolerability, ask about symptoms, and confirm that the medication is working alongside the rest of the regimen.

A Final Note From Me

When I think about which medications I've started prescribing in the past decade that have actually changed outcomes for my patients, SGLT2 inhibitors are near the top of the list. The trials are clean, the benefit is meaningful, and the side effect profile is manageable. Most of my patients who start one of these drugs notice nothing at all in terms of how they feel day to day. The benefit shows up in the form of fewer hospitalizations, slower kidney decline, and longer lives, which is the kind of benefit we like in cardiology even when it's invisible to the patient.

The diabetes label on the bottle is a historical accident at this point. The drugs were approved for diabetes because that's where the development pathway started, and the FDA labeling system is slow to catch up to evolving evidence. Insurance prior authorizations sometimes still ask for an A1c or a diabetes diagnosis. We work around it with the right diagnostic codes (heart failure, CKD with proteinuria), and most insurers cover the medication appropriately when the indication is documented. If you've been told you don't qualify because you don't have diabetes, that's usually a paperwork issue rather than a medical one, and it's worth pushing back.

If you've been prescribed an SGLT2 inhibitor and you're confused about why, the answer is almost always that your cardiologist or nephrologist has identified a condition that benefits from the drug regardless of your blood sugar. Heart failure, kidney disease, and certain combinations of cardiovascular risk are the usual reasons. Ask the question. Get the answer in plain language. Take the medication as prescribed, watch for the side effects we've discussed, hold it during sick days and before surgery, and come back to clinic if anything feels off. The class has earned its place in modern cardiology, and the patients who take these drugs as part of a larger plan tend to do better than the patients who don't.

References

1. Zinman, Bernard, Christoph Wanner, John M. Lachin, et al. "Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes." New England Journal of Medicine 373, no. 22 (2015): 2117-2128.

2. McMurray, John J. V., Scott D. Solomon, Silvio E. Inzucchi, et al. "Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction." New England Journal of Medicine 381, no. 21 (2019): 1995-2008.

3. Packer, Milton, Stefan D. Anker, Javed Butler, et al. "Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure." New England Journal of Medicine 383, no. 15 (2020): 1413-1424.

4. Anker, Stefan D., Javed Butler, Gerasimos Filippatos, et al. "Empagliflozin in Heart Failure with a Preserved Ejection Fraction." New England Journal of Medicine 385, no. 16 (2021): 1451-1461.

5. Solomon, Scott D., John J. V. McMurray, Brian Claggett, et al. "Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction." New England Journal of Medicine 387, no. 12 (2022): 1089-1098.

6. Heerspink, Hiddo J. L., Bergur V. Stefansson, Ricardo Correa-Rotter, et al. "Dapagliflozin in Patients with Chronic Kidney Disease." New England Journal of Medicine 383, no. 15 (2020): 1436-1446.

7. The EMPA-KIDNEY Collaborative Group, William G. Herrington, Natalie Staplin, Christoph Wanner, et al. "Empagliflozin in Patients with Chronic Kidney Disease." New England Journal of Medicine 388, no. 2 (2023): 117-127.

8. Heidenreich, Paul A., Biykem Bozkurt, David Aguilar, et al. "2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines." Journal of the American College of Cardiology 79, no. 17 (2022): e263-e421.

9. Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group. "KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease." Kidney International 102, no. 5S (2022): S1-S127.

10. Neal, Bruce, Vlado Perkovic, Kenneth W. Mahaffey, et al. "Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes." New England Journal of Medicine 377, no. 7 (2017): 644-657.

Published on damianrasch.com. The above information was composed by Dr. Damian Rasch, drawing on individual insight and bolstered by digital research and writing assistance. The information is for educational purposes only and does not constitute medical advice.