Do diabetes mellitus (DM) medications cause orthopnea (shortness of breath while lying down)?

From the Guidelines

Diabetes medications generally do not cause orthopnea (difficulty breathing when lying flat), but certain medications like thiazolidinediones can indirectly contribute to breathing difficulties by causing fluid retention, which may exacerbate heart failure symptoms in susceptible individuals. Orthopnea is typically associated with heart failure or other cardiovascular conditions, rather than being a direct side effect of diabetes medications. According to a recent study published in Circulation in 2019 1, thiazolidinediones (TZDs) are associated with an increased risk of heart failure events, which could potentially lead to orthopnea.

Some key points to consider:

• Thiazolidinediones, such as pioglitazone, can cause fluid retention, which may worsen heart failure symptoms in patients with pre-existing heart failure 1.
• Insulin therapy, especially at high doses, can also cause fluid retention in some patients, potentially contributing to breathing difficulties.
• The 2019 ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases recommend avoiding thiazolidinediones in patients with diabetes who are at risk of heart failure or have previous heart failure 1.
• Patients with diabetes who experience new or worsening orthopnea should seek medical attention promptly, as this symptom could indicate the development or worsening of heart failure, which is more common in people with diabetes.

It's essential for patients with diabetes to monitor their symptoms closely, maintain good glycemic control, and follow their prescribed medication regimen. Any concerns about medication side effects or new symptoms should be discussed with their healthcare provider, who may need to adjust the treatment plan or investigate other potential causes of orthopnea. The American Heart Association and the American Diabetes Association have also issued a consensus statement on the use of thiazolidinediones in patients with diabetes, highlighting the importance of careful patient selection and monitoring for signs of heart failure 1.

From the FDA Drug Label

Patients who experience an unusually rapid increase in weight or edema or who develop shortness of breath or other symptoms of heart failure while on ACTOS should immediately report these symptoms to their physician In a 16-week, placebo-controlled ACTOS plus insulin trial (n=379), 10 patients treated with ACTOS plus insulin developed dyspnea and also, at some point during their therapy, developed either weight change or edema.

Orthopnea is not directly mentioned in the provided drug labels. However, shortness of breath is mentioned as a symptom that patients should report to their physician, and dyspnea (difficulty breathing) is reported in patients treated with ACTOS plus insulin.

• The labels do not provide a direct link between diabetes mellitus medications, specifically pioglitazone, and orthopnea.
• The information provided does not support a conclusion that diabetes mellitus medications cause orthopnea. 2 2

From the Research

Diabetes Mellitus Medications and Orthopnea

• Orthopnea, or shortness of breath while lying down, can be a symptom of various conditions, including heart failure, which is a potential side effect of some diabetes medications 3.
• Thiazolidinediones (TZDs), a class of diabetes medications, can cause fluid retention, leading to edema and congestive heart failure (CHF), which may result in orthopnea 3.
• The frequency of peripheral edema associated with TZDs is approximately 5% when used in mono- or combination oral therapy, and about 15% when used with insulin 3.
• Other diabetes medications, such as sulphonylureas, glitazones, and gliptins, have various side effects, but orthopnea is not explicitly mentioned as a common adverse effect 4.
• However, glitazones have a clearly unfavorable harm-benefit balance, potentially causing fractures, heart failure, and other cardiovascular events, which may indirectly contribute to orthopnea 4.
• The combination of metformin with certain hypertensive drugs, such as angiotensin II receptor antagonists or angiotensin-converting enzyme inhibitors (ACEIs), may synergistically improve glucose absorption, but the risk of orthopnea is not directly addressed 5.

Management and Monitoring

• Patients with type 2 diabetes are at high risk of macrovascular complications, including myocardial infarction, stroke, and cardiovascular mortality, which may be exacerbated by certain diabetes medications 6.
• Monitoring and addressing potential drug-drug interactions, such as those between diabetic and hypertensive drugs, is crucial to prevent life-threatening complications, including orthopnea 5.
• The management of orthopnea related to diabetes medications may involve adjusting the medication regimen, using diuretic agents, or implementing other strategies to mitigate fluid retention and heart failure 3.