The Best Diabetes Medication for Heart Failure

SGLT2 inhibitors are, by a wide margin, the best diabetes medication for people with heart failure. Drugs in this class, including dapagliflozin (Farxiga) and empagliflozin (Jardiance), have consistently cut heart failure hospitalizations and cardiovascular death across dozens of trials, regardless of whether the patient’s heart failure involves a weak pumping muscle or a stiff one. No other class of glucose-lowering drug comes close in head-to-head comparisons, and the benefits hold even for people who don’t have diabetes at all, which hints at something deeper than blood sugar control.

Why SGLT2 Inhibitors Stand Apart

A large meta-analysis pooling data from heart failure, diabetes, and kidney disease trials found that SGLT2 inhibitors reduced the combined risk of heart failure hospitalization and cardiovascular death by about 24% in people with heart failure, with a 16% reduction in cardiovascular death specifically.¹ Those benefits were consistent whether patients had reduced or preserved pumping function, whether they had type 2 diabetes or not, and whether they also had chronic kidney disease.

Network meta-analyses comparing all the newer diabetes drug classes reinforce the point. In one analysis of over 170,000 participants across 91 trials, SGLT2 inhibitors ranked at the top for heart failure prevention with a probability of roughly 93%, while thiazolidinediones (the glitazones) sat at the very bottom.² A separate network meta-analysis found that SGLT2 inhibitors cut heart failure hospitalization risk by roughly 44% compared with placebo, outperforming both GLP-1 receptor agonists and DPP-4 inhibitors in direct pairwise comparisons.³

Evidence in Reduced Versus Preserved Ejection Fraction

Heart failure is broadly split into two types based on how well the left ventricle pumps. In heart failure with reduced ejection fraction (HFrEF), the muscle is weakened. In heart failure with preserved ejection fraction (HFpEF), the muscle squeezes normally but is stiff and doesn’t relax properly. For decades, the HFpEF category had almost no treatments that reliably worked, which made the SGLT2 inhibitor data especially striking.

In HFrEF, the evidence is robust. A retrospective cohort study following patients over three years found that those on an SGLT2 inhibitor had significantly fewer heart failure hospital admissions than those not taking one, with about a 39% lower hazard of being hospitalized for heart failure.⁴

In HFpEF, the EMPEROR-Preserved trial showed that empagliflozin reduced the composite of cardiovascular death or heart failure hospitalization by 21%, driven mainly by a 29% lower risk of hospitalization. Cardiovascular death alone was not significantly different between groups, but fewer hospital stays is a meaningful win in a condition where every admission chips away at quality of life.⁵ A trial of dapagliflozin in chronic HFpEF showed improvements that patients could feel: symptom scores improved, physical limitations decreased, and six-minute walk distance increased by about 20 meters after 12 weeks, a proportionally large gain given how limited these patients were at baseline.⁶

How SGLT2 Inhibitors Help the Heart

These drugs were originally designed to lower blood sugar by blocking glucose reabsorption in the kidneys, which sends excess sugar into the urine. But the cardiac benefits appear to involve mechanisms well beyond glucose control. Research points to direct effects on the heart itself: reduced inflammation, lower oxidative stress, improved sodium and calcium handling inside heart cells, and better mitochondrial energy production.⁷ Disturbances in those pathways drive the endothelial dysfunction, cardiac stiffness, and rhythm problems that make heart failure worse.

SGLT2 inhibitors also appear to shift the body’s metabolism in ways that mimic nutrient deprivation: increased ketone production, higher erythropoietin levels, and ramped-up autophagy (the cell’s cleanup process). Changes in iron handling may also contribute to improved cardiac energy supply.⁸ These effects help explain why the drugs work in people without diabetes: the heart benefits are largely independent of blood sugar.

The Benefits Hold Without Diabetes

One of the most important findings in this area is that you don’t need diabetes for SGLT2 inhibitors to protect your heart. In the DAPA-HF trial, dapagliflozin reduced the primary outcome to the same degree in people without diabetes as in those with it, and the benefit held even in people with completely normal blood sugar levels, not just prediabetes.⁹

A meta-analysis of four randomized trials in over 10,600 nondiabetic heart failure patients confirmed a 22% reduction in the composite of worsening heart failure or cardiovascular death with SGLT2 inhibitors versus placebo.¹⁰ A separate systematic review found a nearly identical 20% relative risk reduction.¹¹ Both dapagliflozin and empagliflozin now carry regulatory approvals for heart failure that do not require a diabetes diagnosis. If you have heart failure, the question of whether you “also” have diabetes is almost beside the point when it comes to these drugs.

Where Other Diabetes Drugs Fit In

If SGLT2 inhibitors are the clear frontrunner, the rest of the field sorts out in a surprisingly uneven way. Some classes are safe but unexciting for the heart, some show emerging promise, and one is genuinely dangerous.

Metformin

For years, doctors were actually told not to give metformin to people with heart failure because of a theoretical risk of lactic acidosis. That warning turned out to be overblown. A systematic review of observational studies involving about 34,000 patients found that metformin was associated with a roughly 20% lower mortality risk compared with other treatments (mostly sulfonylureas), with no increased risk of lactic acidosis.¹² A study of older adults hospitalized for heart failure found that metformin initiation was independently linked to better 12-month outcomes, particularly in patients with an ejection fraction above 40%.¹³ Metformin is safe and inexpensive, but it doesn’t deliver the kind of dramatic heart failure protection that SGLT2 inhibitors do. Think of it as a reasonable background diabetes drug that won’t make heart failure worse.

GLP-1 Receptor Agonists

Drugs like semaglutide (Ozempic, Wegovy) and tirzepatide (Mounjaro, Zepbound) have generated enormous interest, especially for HFpEF in people who are overweight or obese. In trials like STEP-HFpEF and SUMMIT, semaglutide and tirzepatide produced substantial weight loss (around 13%), improved six-minute walk distance by 20 to 26 meters, and boosted quality-of-life scores by roughly 16 to 20 points. Both drugs also cut markers of systemic inflammation by about 40%.¹⁴ The improvement in symptoms and physical function is real and clinically meaningful, particularly for obese patients with HFpEF, where excess body mass is a core driver of the disease.¹⁵

That said, GLP-1 receptor agonists have not shown the same magnitude of benefit as SGLT2 inhibitors on hard outcomes like heart failure hospitalization. In head-to-head network comparisons, SGLT2 inhibitors consistently outperform them for that endpoint. GLP-1 receptor agonists may be better thought of as complementary agents, especially valuable in the obese HFpEF population where weight loss itself can relieve symptoms.

Thiazolidinediones

Pioglitazone and rosiglitazone are the drugs to actively avoid if you have heart failure. Thiazolidinediones cause fluid retention by increasing sodium and water reabsorption in the kidneys, which can trigger or worsen heart failure.¹⁶ In the large network meta-analysis, thiazolidinediones ranked dead last for heart failure risk among all diabetes drug classes.¹⁷ If you have heart failure and your regimen still includes a glitazone, that conversation with your doctor should happen soon.

DPP-4 Inhibitors and Sulfonylureas

DPP-4 inhibitors (sitagliptin, saxagliptin, alogliptin) are mostly neutral for the heart, though saxagliptin showed a small signal toward increased heart failure hospitalizations in the SAVOR-TIMI 53 trial.¹⁸ They don’t offer the heart failure protection that SGLT2 inhibitors provide and sit in the middle of the pack.

Sulfonylureas and insulin are older agents that can cause hypoglycemia. In patients with heart failure and cardiovascular disease, low blood sugar episodes are linked to dangerous ventricular arrhythmias, with patients who experienced hypoglycemia showing a significantly higher burden of ventricular tachycardia.¹⁹ That risk gives an added reason to prefer drugs with low hypoglycemia potential, like SGLT2 inhibitors and GLP-1 receptor agonists, in people with heart failure.²⁰

Combining SGLT2 Inhibitors With GLP-1 Receptor Agonists

Because SGLT2 inhibitors and GLP-1 receptor agonists work through different mechanisms, researchers have looked at whether using both together offers additional benefit. The early evidence suggests it does. A systematic review and meta-analysis of cohort studies found that combination therapy was associated with a roughly 33% lower risk of heart failure hospitalization compared with either drug used alone.²¹ A separate meta-analysis reported significant reductions in both mortality and hospitalizations with combined therapy, though at the cost of a modest uptick in gastrointestinal side effects, the nausea and stomach upset that GLP-1 receptor agonists are known for.²²

This combination approach is gaining traction in clinical practice for patients with type 2 diabetes and high cardiovascular risk. The two classes together address blood sugar, weight, blood pressure, and cardiovascular protection through complementary pathways.²³ Cost remains a significant barrier, since both classes are branded medications.

Side Effects to Know About

SGLT2 inhibitors are well tolerated overall. A meta-analysis focused on heart failure patients found that serious adverse events were actually lower in the SGLT2 inhibitor group compared with placebo. The drugs also appeared protective against acute kidney injury. The main trade-offs are genital yeast infections (more common because excess sugar in the urine creates a friendly environment for yeast), urinary tract infections, and episodes of low blood pressure.²⁴

Another meta-analysis of heart failure trials found no significant increase in amputations, severe low blood sugar, dangerous drops in blood pressure, ketoacidosis, or genital infections compared with placebo, and confirmed the protective effect against serious adverse events and kidney injury.²⁵ The two meta-analyses disagree slightly on infections, probably reflecting differences in which trials were included and how events were counted. In practice, genital infections are the most common complaint and are usually mild and treatable. The low blood pressure risk matters more for heart failure patients who are already on diuretics and blood pressure medications, so your doctor may adjust those doses when starting an SGLT2 inhibitor.

Do These Drugs Work Equally in Men and Women?

Women have been underrepresented in heart failure trials for decades, which always raises the question of whether findings in mostly male study populations carry over. For SGLT2 inhibitors, the answer appears to be yes. A meta-analysis of heart failure trials found that both men and women experienced significant reductions in the composite of cardiovascular death or heart failure hospitalization, with hazard ratios of 0.77 for men and 0.75 for women.²⁶ A broader meta-analysis covering nearly 85,000 patients across multiple heart failure drug classes found that guideline-directed therapies, SGLT2 inhibitors included, reduced cardiovascular events to a similar degree in women as in men with HFrEF.²⁷

An Australian population-based study comparing SGLT2 inhibitors with GLP-1 receptor agonists found some nuances by sex: SGLT2 inhibitors reduced major cardiovascular events more clearly in men overall, but the benefit was present in both men and women aged 65 and older, in men with baseline heart failure, and in women with established cardiovascular disease.²⁸ The overall message is reassuring: these drugs are not a “men only” benefit.

Frailty and Older Adults

Heart failure patients tend to be older and often frail, which raises practical concerns about adding another medication. In the EMPEROR-Preserved trial, researchers specifically looked at whether empagliflozin’s effects held across different levels of frailty. Not only did the drug work in frailer patients, but empagliflozin-treated patients were actually more likely to shift to a lower frailty category over a year of follow-up compared with those on placebo.²⁹ The benefit grew over time, with the odds of being less frail increasing at 12, 32, and 52 weeks. That finding matters because frailty in heart failure is not just an abstract marker; it predicts falls, hospitalizations, and death. A drug that might actually push frailty in the right direction, rather than just not making it worse, is unusual.

Cost and Access

The clinical evidence for SGLT2 inhibitors is strong, but the price tag has been a real obstacle. These are branded medications, and for patients without good insurance coverage, the out-of-pocket cost can be steep. A systematic review of economic evaluations found that dapagliflozin was cost-effective for HFrEF in 14 countries, and empagliflozin was similarly cost-effective for HFrEF across all studies examined. The picture was more mixed for HFpEF: empagliflozin was deemed cost-effective in some countries but not in others, including the United States and Thailand.³⁰ Generic versions of dapagliflozin and empagliflozin are starting to reach the market in some regions, which should improve access. In the meantime, manufacturer copay cards and patient assistance programs can sometimes bridge the gap, though navigating those programs can be its own challenge.