Which diabetic medication causes heart failure?

Diabetes is a chronic condition that affects how the body regulates blood sugar levels. Over time, high blood sugar levels can damage blood vessels and nerves, leading to complications like heart disease. Many medications are available to help manage diabetes, but some have been linked to an increased risk of heart failure. This article reviews the evidence on which diabetes drugs may contribute to heart failure.

Some key questions covered in this article include:

– What is heart failure and what causes it?

Heart failure is a condition where the heart cannot pump enough blood and oxygen to meet the body’s needs. It can be caused by coronary artery disease, high blood pressure, or diabetes complications among other factors.

– How might diabetes medications lead to heart failure?

Some diabetes drugs can increase fluid retention, weight gain, and heart rate, potentially stressing the heart over time. They may also interact with heart medications like diuretics.

– Which diabetes medications have the strongest link to heart failure?

Thiazolidinediones (TZDs) like pioglitazone have the strongest evidence connecting them to heart failure risk.

– What do doctors recommend to lower heart risks from diabetes drugs?

Experts suggest avoiding TZDs in patients with heart failure. For other diabetes medications, doctors balance heart failure risks against glucose control benefits.

What is Heart Failure?

Heart failure is a serious medical condition that occurs when the heart cannot pump enough blood and oxygen to meet the body’s metabolic demands. It leads to fatigue, shortness of breath, fluid buildup, and other symptoms. About 6.5 million adults in the U.S. have heart failure.

With heart failure, the heart’s pumping chambers (ventricles) are not able to fill up with or eject blood effectively. This reduces cardiac output, which is the amount of blood pumped from the heart each minute. There are two main types of heart failure:

– Systolic heart failure – Occurs when the left ventricle cannot contract normally to eject enough blood. This is the most common type.

– Diastolic heart failure – Happens when the left ventricle does not relax as it should between beats. This impairs its ability to fill with blood.

Some causes and risk factors for heart failure include:

– Coronary artery disease – Plaque buildup narrowing the arteries can limit blood supply to the heart muscle.

– High blood pressure – Increased pressure strains the heart and blood vessels.

– Diabetes – High blood sugar damages blood vessels and the heart over time.

– Obesity

– Sleep apnea

– Excess alcohol use

– Family history of heart disease

– Smoking

– Previous heart attack

The main symptoms of heart failure include:

– Shortness of breath, especially with activity or exercise

– Fatigue and weakness

– Swelling (edema) in the legs, ankles, feet, and sometimes the abdomen

– Rapid or irregular heartbeat

– Reduced ability to exercise without getting tired or short of breath

– Persistent cough or wheezing with white or pink phlegm

– Increased need to urinate at night

– Confusion, impaired thinking

– Nausea, lack of appetite, abdominal pain

Treatment for heart failure aims to improve quality of life and slow the progression of the disease. Medications like ACE inhibitors, beta blockers, and diuretics help manage symptoms and reduce strain on the heart. Lifestyle changes such as dietary sodium restriction, exercise, and smoking cessation are also important. In severe cases, devices like pacemakers or implantable cardioverter defibrillators (ICDs) may be necessary.

How Diabetes Medications Can Lead to Heart Failure

Diabetes contributes significantly to the risk and progression of heart failure. It does this through both direct and indirect mechanisms:

– High blood glucose levels damage blood vessels, including the arteries supplying the heart. This accelerates atherosclerosis and coronary artery disease.

– Uncontrolled diabetes can damage the nerves supplying the heart muscle, leading to abnormalities in heart rate and function.

– Diabetes often coexists with other heart failure risk factors like high blood pressure and obesity.

Some diabetes medications can also negatively impact the heart, especially in susceptible individuals:

– Certain drugs like TZDs can increase fluid retention in the body, placing strain on the heart.

– Some diabetes medications lead to weight gain, which raises heart failure risks.

– A few agents may increase heart rate to some degree, causing the heart to work harder.

– Interactions with common heart medications like diuretics or ACE inhibitors can occur.

Doctors have to balance tight blood sugar control with potential heart risks when prescribing anti-diabetic medications. Individual patient factors also play a role. Those with existing heart disease or who are at high cardiovascular risk require special consideration.

Diabetes Medications Linked to Heart Failure

Several classes of diabetes medications have been associated with higher heart failure risk, but the strength of evidence varies. Here is an overview of the major drug classes and their potential connection to heart failure.


Thiazolidinediones (TZDs), including rosiglitazone (Avandia) and pioglitazone (Actos), are known as “insulin sensitizers” – they make the body more responsive to insulin’s effects. However, their use has declined over the past decade after studies showed links to heart failure:

– A 2007 meta-analysis of 42 trials found pioglitazone was associated with a significant increase in the risk of serious heart failure events compared to placebo or other diabetes drugs.

– The PROactive study in 2005 first raised concerns about heart failure risk with pioglitazone. Heart failure was more common in the pioglitazone group (5.7% vs. 4.1% with placebo).

– Rosiglitazone has also been connected to higher odds of heart failure versus placebo or metformin in meta-analyses.

– Both drugs can lead to fluid retention, which may precipitate heart failure in at-risk people.

Due to these risks, TZDs are not recommended as first-line diabetes treatment. Pioglitazone still has a role in combination therapy but is typically avoided in patients with heart failure.


Sulfonylureas, including glimepiride (Amaryl), glipizide (Glucotrol), and glyburide (Micronase), stimulate the release of more insulin from the pancreas. A few studies have linked them to heart failure:

– A 2009 study of over 16,000 diabetic veterans found sulfonylurea monotherapy was associated with a 20% higher risk of heart failure hospitalization or death compared to metformin monotherapy.

– Analyses of two clinical trials found higher heart failure among those treated with glyburide versus placebo or other drugs. However, the absolute risk was low.

– Sulfonylureas can sometimes lead to hypoglycemia. Severe low blood sugar episodes trigger neurohormonal and ischemic stress on the myocardium.

Overall, evidence suggests sulfonylureas may modestly raise heart failure risk. Their use is limited in advanced heart failure.


Meglitinides such as repaglinide (Prandin) and nateglinide (Starlix) also stimulate insulin secretion but are shorter-acting than sulfonylureas. Data on their heart failure risk is limited:

– A few analyses of small studies suggest meglitinides may increase heart failure risk similarly to sulfonylureas. However, the evidence is not robust.

– Like sulfonylureas, they can cause hypoglycemia which stresses the heart at very low glucose levels.

– Overall, there is no conclusive evidence that meglitinides raise heart failure risk substantially on their own. However, caution is still warranted in people with heart failure.


Insulin therapy is essential for many patients with type 1 diabetes and advanced type 2 diabetes. But insulin use has also been associated with heart failure risk:

– A large study of over 130,000 diabetic veterans found new insulin use combined with poor glycemic control boosted heart failure hospitalization risk by over 80% compared to oral medications.

– Insulin may increase fluid retention, especially when blood glucose levels swing from high to low.

– Again, hypoglycemia triggered by excessive insulin can indirectly strain the heart.

For most diabetic patients, the benefits of insulin for glucose control outweigh the potential small risks. But care should be taken to avoid low blood sugars.

GLP-1 Receptor Agonists

Glucagon-like peptide-1 (GLP-1) agonists such as liraglutide (Victoza) and exenatide (Byetta, Bydureon) stimulate insulin release while suppressing glucagon. They do not appear to raise heart failure risk:

– The LEADER trial of liraglutide in over 9,000 patients with high cardiovascular risk found no increase in heart failure hospitalization versus placebo. Heart failure death rates were actually lower with liraglutide.

– Other studies of exenatide, lixisenatide, and semaglutide also report neutral or potential beneficial cardiovascular effects.

– GLP-1 drugs promote some weight loss rather than gain, which likely offsets any fluid retention effects.

For most experts, GLP-1 agonists are the preferred injectable anti-diabetic medication for patients with heart failure given their reassuring safety data.

DPP-4 Inhibitors

DPP-4 inhibitors like sitagliptin (Januvia), saxagliptin (Onglyza), and linagliptin (Tradjenta) prolong GLP-1 activity levels in the body by preventing its breakdown. But studies differ on their potential heart failure risks:

– The SAVOR-TIMI 53 trial found a 27% increase in hospitalization for heart failure among diabetic patients treated with saxagliptin versus placebo. The reason is unclear.

– Several other large trials of sitagliptin, alogliptin, and linagliptin showed no increased risk of heart failure versus placebo.

– A 2019 meta-analysis concluded that DPP-4 inhibitors as a class do not significantly raise heart failure risk compared to placebo or other diabetes medications. Saxagliptin appears to confer the greatest risk.

Overall, most DPP-4 inhibitors seem to have a neutral effect on heart failure risk in diabetes. Saxagliptin may be an exception.

SGLT2 Inhibitors

SGLT2 inhibitors such as canagliflozin (Invokana), empagliflozin (Jardiance), and dapagliflozin (Farxiga) reduce blood glucose by increasing urinary glucose excretion. Remarkably, they may reduce heart failure risk:

– In the EMPA-REG OUTCOME trial, empagliflozin cut cardiovascular death and heart failure hospitalizations by over 30% compared to placebo in type 2 diabetics with high cardiovascular risk.

– Canagliflozin showed a similar 33% reduction in heart failure hospitalizations relative to placebo in the CANVAS program study.

– Several other trials have also reported heart failure benefits with SGLT2 inhibitors. Reductions in fluid overload and systemic vascular resistance may play a role.

– As a result, SGLT2 inhibitors are emerging as first-line diabetes treatments for many patients with heart failure.


Metformin is the most commonly prescribed initial oral diabetes drug. Studies consistently show metformin does not increase heart failure risk at standard doses:

– A 2012 meta-analysis of over 70,000 patients found no increased risk of heart failure hospitalization or mortality linked to metformin versus comparator drugs or control groups.

– The UKPDS trial, which followed patients for 10 years, found no difference in heart failure rates with intensive metformin therapy versus standard care.

– Metformin is not associated with hypoglycemia or significant weight changes that might impact heart failure risk.

Due to its glucose-lowering effectiveness, excellent safety profile, and low cost, metformin remains the first-line drug for type 2 diabetes unless contraindicated.

Recommendations for Diabetes Drugs in Patients with Heart Failure

Selecting optimal anti-diabetic medications for patients with comorbid heart failure requires balancing heart risks with glucose control benefits on a case-by-case basis. However, experts offer some general recommendations:

Avoid TZDs

Given the consistent evidence linking TZDs to heart failure exacerbation, most guidelines strongly recommend avoiding both pioglitazone and rosiglitazone in patients with established heart failure. The risks generally outweigh the glucose management benefits in this population.

Use Insulin Carefully

Insulin remains an indispensable treatment for many diabetic patients, including those with heart failure. However, steps should be taken to minimize hypoglycemia and fluid retention. Basal insulins like glargine (Lantus) and detemir (Levemir) are preferred over short-acting insulins.

Favor GLP-1 Receptor Agonists

For patients requiring injectable anti-diabetic medications, GLP-1 receptor agonists are the first choice given clinical trials demonstrating cardiovascular safety and possible benefits. They offer effective glycemic control without hypoglycemia or weight gain risks.

Consider SGLT2 Inhibitors

Growing evidence suggests SGLT2 inhibitors like empagliflozin and canagliflozin may reduce major heart failure events in diabetic patients. They are emerging as a first-line treatment when metformin alone is inadequate for glucose control.

Avoid Saxagliptin

Among DPP-4 inhibitors, saxagliptin appears unique in its increased association with heart failure hospitalization. Sitagliptin or linagliptin may be safer choices within this medication class for patients with heart failure.

Use Sulfonylureas and Meglitinides With Caution

Sulfonylureas and meglitinides should be used judiciously and at lower doses in patients with heart failure given the hypoglycemia and limited heart failure safety data. Glycemic targets may need to be less intensive.

Continue Metformin If Tolerated

Metformin remains first-line in diabetes even when heart failure is present. It has an excellent safety profile without concerns for heart failure exacerbation at standard doses. Renal function and risk for lactic acidosis must be monitored.

Key Takeaways on Diabetes Drugs and Heart Failure

In summary, here are some of the key points on diabetes medications and their connection to heart failure:

– Thiazolidinediones (especially pioglitazone) have the strongest evidence linking them to heart failure exacerbation and should be avoided.

– Insulin, sulfonylureas, and meglitinides may modestly increase heart failure risk, primarily through hypoglycemia. Their use requires caution and dose adjustment.

– Saxagliptin appears unique among DPP-4 inhibitors in elevating heart failure hospitalization risk and should not be preferred.

– GLP-1 receptor agonists and SGLT2 inhibitors appear to have beneficial or at least neutral effects on heart failure outcomes.

– Metformin remains first-line and safe unless contraindicated or poorly tolerated.

– Overall, diabetes treatment in patients with heart failure demands a patient-centered approach weighing cardiovascular and glycemic control considerations.

The Bottom Line

Managing diabetes in patients with concomitant heart failure presents challenges. Certain anti-diabetic medications like TZDs are clearly associated with heart failure exacerbation and should be avoided. Saxagliptin also raises particular concerns. On the other hand, drugs like metformin, GLP-1 receptor agonists, and SGLT2 inhibitors have a reassuring cardiovascular safety profile and should be favored when appropriate. With careful medication selection guided by patient factors, glycemic control can be balanced with heart failure risks. Ongoing monitoring and coordination between healthcare providers is crucial in this vulnerable population.

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