SGLT2 Inhibitors for Heart Failure and Kidney Disease: When and Why I Prescribe Them

About a decade ago, if you had told me I would be prescribing a diabetes drug to my heart failure patients who do not have diabetes, I would have been skeptical. That is exactly what I do now, multiple times every week. SGLT2 inhibitors started out as medications for type 2 diabetes, and the evidence in heart failure and chronic kidney disease has been so strong that they are now foundational drugs in my preventive and therapeutic cardiology practice. This article covers what these drugs do, why the data changed my prescribing, who benefits most, and what side effects and costs to know about.

The story of SGLT2 inhibitors is a reminder that good science sometimes takes us in unexpected directions. A class designed to help with blood sugar ended up transforming how we treat heart failure and protect kidney function. That is not hyperbole; it is the real outcome of major randomized trials over the past five years.

If your cardiologist has mentioned one of these drugs, or if you are curious about whether you might be a candidate, read on. These medications work through a surprising mechanism, and once you understand it, it will make sense why they help in conditions that look unrelated to diabetes.

What SGLT2 Inhibitors Are and How They Work

The name SGLT2 refers to a protein in your kidneys called sodium-glucose co-transporter 2. Your blood is filtered continuously at the kidneys. That filtered fluid contains glucose, and normally almost all of it is pulled back into the bloodstream by transporters like SGLT2. You do not spill glucose into your urine under normal circumstances.

SGLT2 inhibitors block that pullback. They cause glucosuria, meaning glucose ends up in your urine rather than reabsorbed. That might sound wasteful, and in a sense it is. You lose calories as glucose in the urine. It turns out the downstream effects of this simple change are profoundly good for the heart and the kidneys.

The drugs in this class that I prescribe most often are empagliflozin (Jardiance), dapagliflozin (Farxiga), canagliflozin (Invokana), and ertugliflozin (Steglatro). They work through the same SGLT2 mechanism and differ in potency, tolerability, and the strength of the evidence for specific uses.

The downstream effects come from osmotic pressure. When glucose is in the tubular fluid, it pulls water with it. Water cannot be reabsorbed passively if glucose is holding it there. The result is a mild diuretic effect. Your blood volume shifts slightly. Your kidneys respond to that shift through a built-in feedback system that relaxes the tiny arterioles going to the kidney filter, lowering the pressure inside the filter. Lower filter pressure means less protein leak and less slow damage to the nephron. Meanwhile, your heart works against lower filling pressure, which helps decompress the heart in heart failure. That is why one drug helps both the heart and the kidneys.

The Major Trials That Changed Everything

The evidence base for SGLT2 inhibitors is unusually robust for a cardiovascular drug class. Let me walk you through the key trials because they are the reason I prescribe these drugs so widely.

EMPA-REG OUTCOME (2015) studied empagliflozin in patients with type 2 diabetes and established cardiovascular disease. The headline result was a 14 percent reduction in the three-point combined endpoint of cardiovascular death, heart attack, and stroke (hazard ratio 0.86). The more striking finding was a 35 percent reduction in hospitalizations for heart failure, in patients many of whom had no known heart failure to begin with. That result was unexpected, and it opened the door to studying these drugs in heart failure patients without diabetes.

DAPA-HF (2019) randomized 4,744 patients with heart failure and a reduced ejection fraction (LVEF at or below 40 percent, NYHA class II-IV), with or without diabetes, to dapagliflozin or placebo on top of standard heart failure therapy. Dapagliflozin reduced the combined endpoint of cardiovascular death or worsening heart failure hospitalization by 26 percent (hazard ratio 0.74, 95% CI 0.65-0.85). The benefit appeared within weeks of starting the drug.

EMPEROR-Reduced (2020) tested empagliflozin in 3,730 patients with reduced ejection fraction, a similar design to DAPA-HF. The combined endpoint dropped by 25 percent (hazard ratio 0.75, 95% CI 0.65-0.86). Benefit again within weeks.

EMPEROR-Preserved (2021) extended the indication to heart failure with preserved ejection fraction (HFpEF), the form of heart failure that accounts for roughly half of all HF cases. In 5,988 patients, empagliflozin reduced the combined endpoint by 21 percent (hazard ratio 0.79, 95% CI 0.69-0.90). The benefit was driven almost entirely by a drop in heart failure hospitalization (hazard ratio 0.71); cardiovascular death did not change significantly. It is not as dramatic as in HFrEF, and it was the first positive HFpEF outcomes trial after decades of negative ones.

DELIVER (2022) tested dapagliflozin in 6,263 patients with mildly reduced or preserved ejection fraction (LVEF above 40 percent). The primary combined endpoint dropped by 18 percent (hazard ratio 0.82, 95% CI 0.73-0.92).

On the kidney side, DAPA-CKD (2020) reduced the combined endpoint of a 50 percent decline in kidney function, end-stage renal disease, or renal/cardiovascular death by 39 percent (hazard ratio 0.61) in 4,304 patients with chronic kidney disease and protein in the urine. About a third had no diabetes. EMPA-KIDNEY (2023) extended that result to a broader kidney disease population (6,609 patients, more than half without diabetes) with a 28 percent reduction in the same kind of combined endpoint (hazard ratio 0.72). CREDENCE (2019) showed canagliflozin reduced end-stage renal disease, doubling of creatinine, or renal/cardiovascular death by 30 percent (hazard ratio 0.70) in 4,401 type 2 diabetes patients with protein in the urine who were already on an ACE inhibitor or ARB.

What strikes me about this evidence is the consistency and the speed of benefit. Within weeks, not months. The benefit cuts across ejection fraction categories, across diabetic and non-diabetic populations, and across multiple drugs in the class.

Who Benefits Most

Based on the data above, here is how I think about SGLT2 inhibitors in practice.

Heart failure with reduced ejection fraction (HFrEF). This is where the evidence is strongest and where I prescribe most aggressively. Any patient with HFrEF, diabetic or not, is a candidate unless there is a clear contraindication. I typically start an SGLT2 inhibitor as part of the foundational regimen alongside an ACE inhibitor or ARB (or an ARNI like sacubitril-valsartan), a beta-blocker, and an MRA.

Heart failure with preserved ejection fraction (HFpEF). The benefit is more modest than in HFrEF, and it is real and statistically clear. Many of my older patients with high blood pressure and HFpEF are on an SGLT2 inhibitor.

Chronic kidney disease. SGLT2 inhibitors slow the decline in kidney function and reduce protein in the urine. I prescribe them in patients with diabetic and non-diabetic CKD, especially if there is meaningful protein in the urine. Many of those patients benefit from protection of both the heart and the kidneys at once.

Type 2 diabetes with cardiovascular risk. For patients with type 2 diabetes and established atherosclerosis, prior heart attack, or multiple risk factors, an SGLT2 inhibitor adds meaningful cardiovascular risk reduction.

Prevention in high-risk patients. Some of my patients with high blood pressure, obesity, and a strong family history of early heart disease are on an SGLT2 inhibitor, partly for the mild weight and blood pressure effects and partly because the heart-protective effect may delay frank disease.

How Much Benefit, In Numbers

Let me translate the trial data into numbers that matter in clinic. A patient with HFrEF on dapagliflozin has roughly a 26 percent lower risk of cardiovascular death or heart failure hospitalization versus placebo. That sounds abstract, so here is another way to think about it: if I start ten HFrEF patients on dapagliflozin, I expect to prevent approximately one hospitalization or cardiovascular death over 18 months compared to not treating them.

The hospitalization reduction matters because HF hospitalizations are hard on patients. Days in the hospital, exhausted afterward, real risk of complications. Reducing that chance is valuable even if the absolute numbers sound modest.

In kidney disease, the number needed to treat to prevent one doubling of creatinine or progression to dialysis over a few years runs 10 to 20, depending on your baseline severity and the specific trial. That is meaningful when you are talking about preserving kidney function over a lifetime.

The benefit arrives quickly. In DAPA-HF, measurable separation of the outcome curves appeared within the first four weeks. This is not a drug where you wait months to see if it is working. Most patients feel better, with less shortness of breath and less pillow-stacking at night, within days to weeks.

Kidney Protection and Why It Matters

The kidney protection story is one of the most compelling reasons I reach for these drugs. Chronic kidney disease and heart failure feed each other. Kidney disease raises heart risk; heart disease damages the kidneys. Breaking that cycle at both ends is valuable.

SGLT2 inhibitors reduce protein in the urine substantially, sometimes by 30 to 50 percent. They lower the pressure inside the kidney filter through the natural feedback mechanism I described earlier. They reduce inflammation and scarring. The net result is slower kidney disease progression in patients with diabetic kidney disease, non-diabetic CKD, and in patients with both heart failure and CKD.

In DAPA-CKD, dapagliflozin cut the risk of a 50 percent drop in kidney function, end-stage renal disease, or renal/cardiovascular death by 39 percent (hazard ratio 0.61, 95% CI 0.51-0.72) in patients with CKD and protein in the urine. About 32 percent of the trial population had no diabetes, and the benefit was consistent in diabetic and non-diabetic groups. That consistency is what made the result transformative for a disease that historically had few good options beyond tight blood pressure control and ACE inhibitors.

I counsel my CKD patients that this drug might help preserve their kidney function for years or even decades. That conversation changes lives, since kidney disease progression feels inevitable to many patients once they have been diagnosed.

Who Should Not Take SGLT2 Inhibitors

SGLT2 inhibitors are generally well tolerated, and there are contraindications and cautions.

History of diabetic ketoacidosis. Patients who have had DKA in the past should typically not take SGLT2 inhibitors. The risk of recurrence is higher, and euglycemic DKA (described below) is a concern.

Type 1 diabetes. SGLT2 inhibitors are not approved for type 1 diabetes in the United States, and the risk of euglycemic DKA is real. Research continues, and these drugs remain off-limits in routine practice for type 1.

Severe kidney impairment. Most SGLT2 inhibitors need a baseline filtration rate of 20 to 30 mL/min/1.73m² to work, depending on the agent. Below that, the drug loses its glucose-spilling effect because the kidneys are not filtering enough to spill.

Recent amputation or high amputation risk. Canagliflozin specifically carries an FDA warning about lower-limb amputation. The signal came from the CANVAS trial (Neal, NEJM 2017), where canagliflozin roughly doubled the rate of lower-limb amputation versus placebo (hazard ratio 1.97, 6.3 versus 3.4 per 1,000 patient-years), most of them toe or metatarsal. The signal was not reproduced in the larger CREDENCE trial (hazard ratio 1.11, not significant), and contemporary meta-analyses suggest the CANVAS finding may have been trial-specific. I am still more cautious with canagliflozin in patients with neuropathy, prior amputation, or severe peripheral arterial disease, and the absolute risk is small.

Active genital yeast infection. These drugs increase the risk of yeast infections (explained below), so active infection gets treated before starting.

Acute decompensated heart failure or cardiogenic shock. The mild diuretic effect and reduced preload can be problematic in acute decompensation. These drugs are for chronic heart failure management, not acute hospital care.

Side Effects and How to Manage Them

Most patients tolerate SGLT2 inhibitors well. A few side effects deserve attention.

Genital yeast infections. This is the most common side effect, and it comes directly from the mechanism. You are spilling glucose into urine, and glucose feeds candida. Women get vaginal yeast infections at higher rates, typically 10 to 20 percent in trials. Men can get balanitis. I counsel patients to report this early, since it is easily treated with a topical antifungal cream or oral fluconazole, and the SGLT2 inhibitor does not have to be stopped. Good hygiene helps, including wiping front to back and changing out of damp clothes quickly after exercise.

Euglycemic DKA. This is a rare, serious form of diabetic ketoacidosis where the blood sugar is not dramatically high but the patient is still in ketoacidosis. Higher risk in patients with type 1 diabetes, a prior DKA history, insulin use, pregnancy or recent delivery, critical illness, or upcoming surgery. Symptoms include nausea, vomiting, shortness of breath, fatigue, and abdominal pain. I tell patients to seek immediate care for any of those symptoms and to make sure the treating clinician knows about the SGLT2 inhibitor. Euglycemic DKA is uncommon enough that it does not keep me from using these drugs in appropriate patients, and it is something I watch for.

Volume depletion and lightheadedness. SGLT2 inhibitors cause mild fluid loss. Some patients feel dizzy or lightheaded when standing, especially if they are also on loop diuretics or blood pressure medications. I often reduce other medications slightly when starting an SGLT2 inhibitor, and volume status usually stabilizes after a week or two.

Acute kidney injury. Uncommon, and it has been reported in patients who are severely dehydrated, on NSAIDs, or on ACE inhibitors during an illness. I am cautious in patients with very low kidney function and I emphasize staying well hydrated during acute illness.

Bone fractures. Canagliflozin has been linked to a small increase in lower-limb fracture risk. The mechanism is not fully understood. I take this into account in elderly patients with osteoporosis, and it is not a reason to avoid the drug if the indication is strong.

Fournier's gangrene. An extremely rare but life-threatening perineal infection. Only a handful of cases have been reported in the literature. The FDA has issued a warning, and I do not avoid these drugs because of it. I do counsel patients to seek immediate care for any perineal pain, swelling, redness, or drainage.

Overall, most patients tolerate these drugs very well. Yeast infections are easy to manage, and serious side effects are rare when the drug is used in the right patients.

Dosing and Starting

Dosing varies by drug and by indication.

Empagliflozin. For heart failure, 10 mg once daily. For type 2 diabetes, 10 mg daily (25 mg is available if needed for glucose control).

Dapagliflozin. For heart failure or kidney disease, 10 mg once daily. Straightforward.

Canagliflozin. 100 to 300 mg once daily depending on indication and kidney function. I use it less often than the first two, partly from the CANVAS amputation signal and partly because the heart failure data are less strong.

Ertugliflozin. 5 or 10 mg once daily. This agent arrived later and I have less experience with it, so it is often third or fourth line in my practice.

I usually start at the low dose, watch for tolerability over a week or two, then move to the target dose. I check electrolytes and kidney function within a week or two of starting, especially in older patients and those with kidney impairment.

All of these are once-daily medications, which helps adherence. The benefit goes away if the patient stops taking the drug, so adherence matters.

Cost and Insurance

SGLT2 inhibitors are expensive. A month's supply of brand-name empagliflozin or dapagliflozin costs roughly $300 to $400 out of pocket at retail. Insurance coverage varies widely. Some plans cover them generously under heart failure or kidney disease indications. Others require step-through (you have to try an ACE inhibitor or other first-line agent before they will cover an SGLT2 inhibitor).

Generic versions are starting to appear as patents expire, which will bring costs down. Empagliflozin has generic availability in some regions. Dapagliflozin generics are on the horizon.

If cost is a barrier, I talk with patients about manufacturer patient assistance programs. Eli Lilly, Merck, and Janssen all have programs for uninsured or underinsured patients. GoodRx and other discount programs sometimes help. A mail-order 90-day supply through insurance is often cheaper than retail.

I do not minimize the cost conversation. I frame it this way: if the drug prevents a heart failure hospitalization, that is a several-thousand-dollar savings right there. If it slows kidney disease and delays dialysis, that is tens of thousands of dollars in savings. The upfront cost is high, and the value is often clearly there.

How I Decide Who to Start

The decision to prescribe an SGLT2 inhibitor in my clinic is not formulaic. It depends on several factors.

First, the diagnosis. Is this a clear indication like HFrEF? If yes, they are almost always getting the drug unless there is an absolute contraindication. Is it a softer indication like type 2 diabetes without HF or CKD? Then I think about other risk factors. Hypertension, obesity, CKD stage 3 or worse, prior heart attack, strong family history? The more risk factors, the more likely I recommend one.

Second, what else they are on. Are they already on an ACE inhibitor or ARB, a beta-blocker, and an MRA? If we have room to add a fourth agent and the indication is strong, I add it. Are they on three or four cardiac drugs already? I think about interactions, pill burden, and adherence. Some patients do better reliably on four good drugs than unreliably on seven.

Third, kidney function. If the filtration rate is below 20 to 25 (depending on the agent), the drug will not work well. I do not start it in stage 5 CKD unless a specific new indication has shifted that calculus.

Fourth, symptoms and preferences. Do you want another medication? Do you have a history of yeast infections that would make this harder? Are you pregnant or planning pregnancy? Are there social factors that make adherence hard? A medication you cannot or will not take is worthless.

In practice, the decision usually comes down to: does this patient fit the evidence-based indication, are they medically stable enough to start safely, and is there no absolute contraindication? If yes to all three, we start.

The Bottom Line

SGLT2 inhibitors have moved from niche diabetes drugs to foundational therapy for heart failure and chronic kidney disease. The evidence is strong, the side effects are manageable for most patients, and the benefits arrive quickly. I prescribe them regularly in my HFrEF patients, in many of my HFpEF patients, and in patients with CKD with or without diabetes. The data show they prevent hospitalizations, reduce cardiovascular death, and slow kidney disease progression. Those are not modest gains. They are real improvements in outcomes.

If you are a patient with heart failure or kidney disease, or if you have type 2 diabetes with cardiovascular risk factors, asking your cardiologist whether an SGLT2 inhibitor is right for you is a reasonable conversation. These drugs have changed my practice and improved outcomes for my patients. They will continue to be central to how I manage these conditions for years to come.

Frequently Asked Questions

Do SGLT2 inhibitors actually work if you do not have diabetes?

Yes. The mechanism works independently of blood sugar. Even patients with normal glucose levels benefit from the mild diuretic effect, the blood pressure reduction, the kidney protection, and the heart-remodeling benefits. The trials that proved benefit in heart failure and kidney disease included large numbers of patients without diabetes, and the benefit was just as clear in them.

How quickly do they work?

Quickly. In DAPA-HF, measurable benefit appeared within the first month of treatment. Most patients with heart failure notice easier breathing and less fluid retention within days to weeks. The kidney protective effects take longer to measure and begin working immediately at the cellular level. This is not a drug where you wait months to see if it is helping.

Can I take an SGLT2 inhibitor if I am on dialysis?

No. Once your kidneys are on dialysis, the drug no longer works because there is no glomerular filtration, so glucose cannot spill into urine. These drugs are for patients with some residual kidney function. For dialysis patients with heart failure, other medications take the lead.

What if I have both heart failure and kidney disease?

This is where SGLT2 inhibitors shine. They address both at once. The same mechanisms that protect the heart also protect the kidneys. If you have HF and CKD together, an SGLT2 inhibitor is very likely part of your treatment plan.

Do I need to check my blood sugar more often?

If you have diabetes and are on insulin or a sulfonylurea, yes. SGLT2 inhibitors can lower blood glucose, especially in combination with insulin or a sulfonylurea, and your doctor may reduce the dose of those other drugs. If you are not on diabetes medication, you do not need to check glucose more often.

Can I stop it when I feel better?

No. These drugs work while you are taking them, and the benefit goes away if you stop. Like blood pressure or heart failure medications, the SGLT2 inhibitor is usually a long-term commitment. If you feel better, it is because the drug is working. Stopping it means losing that benefit. Talk to your cardiologist before making any changes.

Are there drug interactions I should worry about?

The main interactions are with other drugs that affect blood pressure, kidney function, or volume status. NSAIDs, ACE inhibitors, and diuretics are commonly used together with SGLT2 inhibitors, and your doctor needs to monitor kidney function and blood pressure. There are no major drug-drug interactions with the SGLT2 inhibitors themselves.

What if I am having surgery?

Talk to your surgeon and cardiologist. There has been concern about peri-operative DKA with SGLT2 inhibitors, so some surgeons ask you to hold the drug for a day or two around surgery. The details depend on the type of surgery and your overall risk profile. Do not stop the drug on your own. Coordinate with your surgical team.

References

1. Zinman, Bernard, Christoph Wanner, John M. Lachin, et al. "Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes (EMPA-REG OUTCOME)." 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 (DAPA-HF)." 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 (EMPEROR-Reduced)." 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 (EMPEROR-Preserved)." 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 (DELIVER)." New England Journal of Medicine 387, no. 12 (2022): 1089-1098.

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

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

8. Perkovic, Vlado, Meg J. Jardine, Bruce Neal, et al. "Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy (CREDENCE)." New England Journal of Medicine 380, no. 24 (2019): 2295-2306.

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

10. Wiviott, Stephen D., Itamar Raz, Marc P. Bonaca, et al. "Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes (DECLARE-TIMI 58)." New England Journal of Medicine 380, no. 4 (2019): 347-357.

11. Heidenreich, Paul A., Biykem Bozkurt, David Aguilar, et al. "2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure." Circulation 145, no. 18 (2022): e895-e1032.

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.