Rybelsus and Depression: Symptoms Reported on Reddit

Rybelsus and Depression are not formally linked in the FDA prescribing information. However, depressive symptoms following the use of the novel GLP-1 agonist, Semaglutide, are being frequently reported.

We reviewed different Semaglutide discussion groups on social media forums to find the association and burden of depressive symptoms in patients who have been prescribed Rybelsus.

Unlike, Ozempic and Wegovy, Rybelsus is administered as an oral pill, and hence the symptoms of anxiety associated with injections (and needles) are not an issue with Rybelsus.

How Patients on Rybelsus Describe Depressive Symptoms:

Patients who were on Rybelsus described their symptoms on social media discussion forums as:

• frustrated or going crazy
• helpless and not optimistic
• in denial and being angry
• still, fingers crossed and waiting
• the medicines are so repulsive to me
• these medicines are counterproductive
• I can not concentrate on my diet
• I am having a very rough time
• I am having a persistent headache
• I can not sleep because of palpitations
• I have a dry mouth and palpitations

Since these were the symptoms as described by the patients, they are not in accordance with the DSM V criteria of depression.

The DSM V Criteria of depression includes any five of the following symptoms over a period of at least two weeks.

1. Low mood most of the day, almost every day
2. Loss of interest in most activities of daily life almost every day
3. Significant weight loss or weight gain without any change in diet
4. Reduction in physical activities and slow down of thoughts as observed by relatives or friends
5. Fatigue and loss of energy
6. A feeling of being worthless and feeling guilt
7. Inability to think, concentrate, and decide
8. thoughts of death, suicidal ideas

Five of the above symptoms with at least one symptom as “low mood” and “loss of interest” fulfills the diagnosis of depression.

Rybelsus and Depression: Can we link the two conditions?

As mentioned above, people on Rybelsus have symptoms that might correspond to the symptoms of depression.

There haven’t been enough studies to determine the association of depression with the use of Rybelsus.

One study found an improvement in the quality of life in patients who were being treated with Semaglutide. It was also noted that the quality of life improved most in the following patients [Ref]:

• Patients who achieved a weight loss of at least 5% or more,
• Patients whose A1C dropped by at least 1% or more,
• Patients who had minimal gastrointestinal side effects,
• Those who did not develop any major adverse cardiovascular outcomes (MACE), and
• Patients who did not develop hypoglycemia

Based on the above observations, the following groups of patients are at risk of developing depression and anxiety when using Rybelsus:

• Intolerant Side effects:

When patients are switching from one kind of diabetes treatment to another, they are usually doing it either to overcome the side effects of the previous medicines or they need better control of their diabetes.

However, Rybelsus is associated with frequent gastrointestinal side effects. Most patients switch or discontinue metformin because of the same side effects.

Experiencing the same side effects with Rybelsus triggers the symptoms of anxiety and stress.

Some patients may develop serious side effects such as MACE (major adverse cardiovascular events), pancreatitis, or thyroid malignancies. These patients can develop depression due to these illnesses.

• Failure to achieve blood sugar targets:

As mentioned above, one of the reasons people switch to Rybelsus is because of uncontrolled blood glucose.

The A1C reduction observed in clinical trials ranged between 1 to 2% with both Rybelsus and metformin.

In one study, the mean HbA1C reduction with metformin was 1.2% after one year (from the baseline A1C of 8.1%) [Ref].

The A1C reduction with Rybelsus ranges between 0.8 to 1.3%. Thus, patients with uncontrolled blood glucose, when switched to Rybelsus, may observe no significant change in their glucose control.

This could be a reason for anxiety and hopelessness in patients. Such patients might get better results with the addition of metformin twice daily or metformin XR once daily at night.

Adding medicines increases the pill burden and the side effects resulting in anxiety and depression.

• Failure to Lose weight with Rybelsus:

One of the reasons patients might switch to Rybelsus is to lose some weight. However, it is important to note that Rybelsus is not approved as weight-loss medicine.

Although the weight loss effects of Rybelsus have been observed to be greater than metformin and Januvia, and equivalent to Jardiance and Liraglutide (Saxenda), some patients might not lose enough weight as per their expectations.

This could lead to symptoms of anxiety and depression.

• Hypoglycemia:

It has been noted that patients who develop frequent hypoglycemia are more prone to have symptoms of anxiety and depression.

Rybelsus can cause hypoglycemia when added to insulin or sulfonylureas. Symptoms of hypoglycemia may mimic a panic attack.

Patients who develop frequent episodes of hypoglycemia have palpitations, cold sweats, and apprehension.

Switching to a new, so-called more potent medicine, might increase their fear of developing more severe hypoglycemia.

It is important to start with a low dose, i.e. 3 mg once daily, and then titrate the dose gradually. In addition, the dose of other diabetes medicines may need to be reduced to avoid hypoglycemia.

• Increase in heart rate with Rybelsus:

In clinical trials, one of the side effects of Rybelsus was tachycardia or increased heart rate. It was observed to be more common in patients who were taking Rybelsus compared to placebo.

The heart rate in patients taking Rybelsus increased by 2 to 4 beats per minute compared with the placebo. Since tachycardia and palpitations are the symptoms of anxiety, patients may attribute these symptoms to anxiety.

This is especially true for patients who have markedly increased heart rates.

To Summarize:

Rybelsus and depression are not formally linked, however, the association may be clinically relevant in a subset of patients who fail to achieve adequate glycemic control, do not lose the expected weight, or develop drug-induced side effects.