AN INTERESTING EXPERIENCE WITH EMPAGLIFLOZIN: UNIDENTIFIED BODY ODOR

Abstract

Context

Sodium-glucose co-transporter 2 inhibitors (SGLT2-I) are a new class of oral antidiabetic drugs.

Objective

Side effects of drugs are frequently encountered with increasing use in clinical practice.

Design/Subjects and Methods

We present a case with an unidentified body odor that has not been described yet in the literature as an adverse effect of SGLT2-I.

Results

A 49-year-old female patient with Type 2 DM was applied to our clinic for routine control. She had been receiving sitagliptin/metformin 50/1000 mg b.i.d. Her fasting plasma glucose was 160 mg/dL and HbA1c was 8%. Empagliflozin 10 mg/day was added to therapy. The patient noticed that two weeks after starting empagliflozin treatment, she began to smell herself and felt a bad/foul odor was released from her body. The patient associated these complaints with the new drug(empagliflozin) stopped two weeks ago. She also stated that all these complaints had disappeared one week after stopping the medication and there were no complaints at the moment.

Conclusions

Here we report an unidentified body odor as a potential empagliflozin-associated adverse event. There was a close temporal relationship between empagliflozin intake and the development and the occurrence of the described odor.

Introduction

Sodium glucose co-transporter 2 inhibitors (SGLT2-I) are a new class of oral antidiabetic drugs that lead to SGLT2 inhibition in the renal proximal tubules, reducing glucose reabsorption from the kidney and increasing glucose excretion (1). Currently there are three SGLT2-I approved by the Food and Drug Administration for mono, dual, and triple therapy: canagliflozin, dapagliflozin and empagliflozin (2). As their mechanism of action is independent of insulin secretion and peripheral insulin sensitivity, they can be potentially used in any stage of Type 2 Diabetes (Type 2 DM). American Diabetes Association (ADA) recommends a SGLT2-I or glucagon-like peptide 1 receptor agonist (GLP-1 RA) as part of the glucose-lowering regimen independent of glycosylated hemoglobin levels (HbA1c) and in consideration of patient-specific factors in patients with type 2 diabetes who have established atherosclerotic cardiovascular disease (ASCVD) or indicators of high risk, established kidney disease, or heart failure (3).

Side effects of drugs are frequently encountered with increasing use in clinical practice. Genitourinary tract infections, risk of volume depletion, orthostatic hypotension, diabetic ketoacidosis, risk of bone fracture (especially with canagliflozin), hyperlipidemia, risk of Fournier’s gangrene and risk of amputation are among the side effects of SGLT2-I reported to date (4).

Herein, we report a case who presented with an unidentified body odor that has not been described yet in the literature as an adverse effect of SGLT2-I.

Case Report

A 49-year-old female patient with Type 2 DM and hyperlipidemia, was visited to our outpatient clinic for periodic evaluation of her chronic conditions. She had no active complaints. She was diagnosed with Type 2 DM about 5 years ago and had been receiving sitagliptin/metformin 50/1000 mg twice a day (b.i.d.). She was also on atorvastatin 10 mg/day treatment due to hyperlipidemia. She did not follow a diet or exercise. She had no history of ASCVD - defined as coronary heart disease, cerebrovascular disease, or peripheral arterial disease. Her last eye examination performed 9 months ago revealed no retinopathy. She had no history of nephropathy or neuropathy.

Her height was 168 cm and her weight was 75 kg with a body mass index of 26.6 kg/m². Her physical examination was normal with 130/80 mmHg blood pressure and 74 beats/min pulse. Laboratory tests revealed normal kidney and liver functions with urea: 24 mg/dL, creatinine: 0.81 mg/dL, estimated glomerular filtration rate (eGFR) 85.88 mL/min/1.73m², aspartate aminotransferase 16 U/L, alanine aminotransferase: 14U/L. She had hyperlipidemia with a total cholesterol value of 216 mg/dL, a trigylceride value of 94 mg/dL, a high density lipoprotein – cholesterol value of 53 mg/dL and a low density lipoprotein value of 144 mg/dL. Proteinuria, erythrocyte or leukocyte were not detected in urine test.

The patient was evaluated with self-monitoring of blood glucose (SMBG). Her fasting blood glucose (FBG) levels ranged between 120-170 mg / dL, and post-prandial glucose (PPG) levels ranged between 160-220 mg/dL. Her fasting plasma glucose (FPG) was 160 mg/dL and HbA1c target was not achieved (HbA1c: 8%) despite being on medication. Empagliflozin 10 mg/day was added to the current treatment (sitagliptin/metformin 50/1000 mg b.i.d). The patient was counseled on diabetic diet and lifestyle recommendations.

She was evaluated in our clinic again 6 weeks after starting empagliflozin with SMBG showed that FBG ranged between 90-140 mg/dL and PPG ranged between 140-200 mg/dL. The patient expressed that she felt better, but two weeks after starting empagliflozin treatment, she noticed a smell on herself and felt a bad/foul odor was released from her body. The patient was questioned for possible side effects of empagliflozin (such as diabetic ketoacidosis, hypoglycemia, genitourinary system infection), but no side effects were evident. We checked her kidney functions, venous blood gas and urine test for possible euglycaemic ketoacidosis. Laboratory tests were normal. There was no ketoacidosis. As we did notice an odor during the examination as described by the patient, we did not pay much attention to the odor complaint. The patient was advised to continue with her current medical treatment, considering that this complaint may not be associated with the treatment. Nevertheless, she was consulted by the dermatology department for the body odor.

The patient stated that the bad odor that started in her body two weeks after starting empagliflozin treatment had not passed, so she had to take a bath all day. The odor came back from her body an hour after the bath. She stated that she felt the odor overall the whole body without any specific localization. There was no odor in the breath, the urine, or the sweat. She did not describe any symptoms such as a sense of sweet or fruity odor on the breath, a sweet or metallic taste in the mouth, or a difference in the smell of urine or sweat that could be found in diabetic ketoacidosis. When asked to describe the odor, she stated that it was in the form of a dry, bitter smell that was difficult to describe. She stated that the odor also disturbs the people around her and her husband did not want to stand next to her or lie in the same bed. Her children were also uncomfortable with being in the same room with her. The patient’s husband confirmed his wife’s strong and unpleasant smell. When he was asked to describe the odor, he stated that it was in the form of mould cheese smell. He could not comment on the origin of the odor. The patient related these complaints with the new drug (empagliflozin).

The patient was re-evaluated 3 months after starting empagliflozin. She had been examined by a dermatologist, but her complaint had not been linked to any medical condition. She declared that she had stopped empagliflozin treatment approximately 15 days ago. She also stated that all these complaints had disappeared 1 week after stopping the medication and there were no complaints at the moment. Her husband also confirmed these findings in the same way.

Meanwhile, laboratory tests revealed that FPG was 120 mg/dL and HbA1c was 7%. Proteinuria, ketone, erythrocyte, leukocyte were not detected in urine test. It was observed that the patient had a decrease of 1 unit in HbA1c compared to 3 months ago. The bad odor disappeared by itself. She felt relieved and stated that she did not want to use that drug (empagliflozin) again. No additional treatment was given and the treatment was continued with sitagliptin/metformin 50/1000 mg b.i.d. Routine control was planned after 3 months with diabetic lifestyle and diet recommendations.

Discussion

Humans emit numerous volatile or non-volatile compounds from different areas of the body that produce odor. Body odor (BO) is an unpleasant smell arising from different parts of body. Perspiration (skin odor), oral cavity (exhaled breath) and human excretions (urine, etc.) are the main resources of BO (5).

Perspiration itself actually has no odor. It is only when sweat encounters bacteria on the skin that a smell can emerge that is considered pathologic and termed bromhidrosis (5,6). Bromhidrosis is divided into apocrine and eccrin variants, depending on the type of sweat gland included. Apocrine glands develop after puberty and are most extensively distributed to axillae, anogenital areas and breasts. The main glands that secrete pheromones appear apocrine glands. Eccrine glands are widely distributed all over the body, where they are involved in thermoregulation through sweat production (6). In this regard, we referred our patient to the dermatology department for these reasons that may cause BO, but no medical condition was diagnosed by the dermatology department.

BO can be triggered by eating spicy or pungent foods such as garlic, curry, onions, and cruciferous vegetables like broccoli, brussels sprouts, and cauliflower. BO may indicate a potentially serious medical conditions such as endocrinologic disorders (overweight, diabetes, overactive thyroid, pituitary gland disorders), gout, tumor, menopause, frostbite, head injury, excessive alcohol consumption, infectious diseases (6). We also questioned our patient about the possibilities listed above, but we could not find a related situation.

Several groups of drugs are known in the literature that can cause BO through excessive sweating such as antidepressant medications (bupropion hydrochloride, venlafaxine hydrochloride ect.), non-steroidal anti-inflammatory drugs (ketoprofen and naproxen), analgesic (codeine), omega-3-acid ethyl esters, leuprolide acetate, topiramate, brivaracetam when used in diabetic patients (7,8).

Here we report an unidentified BO as a potential empagliflozin-associated adverse event. There was a close temporal relationship between empagliflozin ingestion and the development and the occurrence of the described odor. No other factors such as comorbidities, change of nutrition or co-medications which might have also caused this phenomenon were described. In the full prescribing information for empagliflozin, we see that the word of “odor” is mentioned only once (9). This condition is defined as “vaginal odor” that may occur as a result of vaginal yeast infections. Then, when we questioned our patient in this regard, we learned that she did not have such a complaint. Although it is not directly referred to as the word “odor”, it is known that odor may develop in ketoacidosis, which is the known side effect of empagliflozin (9). However, we could not detect ketoacidosis in our patient.

We are aware that there is definitely a limitation in this report. When the patient visited the outpatient clinic again, she had stopped the empagliflozin treatment and her complaint had gone. Due to the subjective nature of the unidentified BO, we had great difficulty in objectively demonstrating this side effect. We explained this situation to the patient and informed her that sharing her complaint would contribute to the literature and we received written consent for publication of this material.

Although we do not know the mechanism of the bad/foul odor that could be related to empagliflozin, as doctors who argue that all literature should be within the limits of evidence-based medicine, we think it would be useful to publish this case as a doctor’s clinical experience.

In conclusion, our report is of clinical importance due to the reporting of a side effect not previously reported.

Conflict of interest

The authors declare that they have no conflict of interest.