Dapagliflozin-induced abnormal uterine bleeding in a patient with dilated cardiomyopathy and chronic heart failure: a case report

Abstract

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are extensively used in the management of heart failure because of their cardiovascular benefits. Adverse drug reactions associated with dapagliflozin include diabetic ketoacidosis, fungal infections, and increased blood glucose concentrations. However, abnormal uterine bleeding is not a known side effect of dapagliflozin. We report a 75-year-old Chinese woman with dilated cardiomyopathy and chronic heart failure who experienced abnormal uterine bleeding while taking dapagliflozin. Notably, cessation of dapagliflozin administration resulted in the disappearance of uterine bleeding. These findings suggest that dapagliflozin possesses additional potential mechanisms, but these mechanisms require further investigation. Furthermore, healthcare professionals should remain vigilant regarding the occurrence of uterine bleeding when prescribing dapagliflozin.

Background

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are effective in preventing cardiovascular death and all-cause mortality, and reducing the risk of worsening heart failure and hospitalization.^1–3 Dapagliflozin has been approved for use in heart failure because of its cardiovascular benefits. Adverse drug reactions associated with dapagliflozin include diabetic ketoacidosis, fungal infections, and increased blood glucose concentrations. However, abnormal uterine bleeding (AUB) is not a known side effect of dapagliflozin. ⁴ To the best of our knowledge, there have been no reports of AUB as an outcome or effect of dapagliflozin administration. We report the case of a 75-year-old woman who experienced repeated episodes of AUB while taking dapagliflozin. Cessation of this treatment resulted in the resolution of her symptoms.

Case report

The reporting of this study conforms to the CARE guidelines. ⁵ The patient provided written informed consent for the treatment.

The patient was a 75-year-old Chinese woman who weighed 64 kg and had previously undergone menopause. She had a medical history of dilated cardiomyopathy and chronic heart failure for more than a decade. She had long-term treatment with furosemide 20 mg once daily, spironolactone 20 mg once daily, metoprolol 23.75 mg (a half-dose of 47.5 mg) once daily and sacubitril/valsartan 50 mg once daily. The patient had poorly controlled heart failure, resulting in frequent hospital readmissions. There was no history of hypertension, diabetes, or mental illness. Her family history was also unremarkable.

The patient presented to the hospital with chest discomfort and bilateral lower limb edema that had worsened over the course of 1 week. Her body weight was 73.2 kg at the time of admission. Blood tests (Table 1) showed heart failure and renal insufficiency, while electrocardiography showed left bundle branch block. Transthoracic echocardiography demonstrated an ejection fraction of 26% and dilation of both left atria and ventricles. Moderate mitral regurgitation and tricuspid regurgitation were also observed along with a moderately increased pulmonary artery pressure of 58 mmHg. Bilateral carotid artery plaque deposits were detected by carotid ultrasound. She was managed for her dilated cardiomyopathy, left bundle branch block, chronic heart failure, and New York Heart Association class IV. She continued to take furosemide, spironolactone, metoprolol, and sacubitril/valsartan at the previously prescribed dosage. Atorvastatin 20 mg once nightly was then prescribed to achieve plaque stabilization. Two days after her admission, she underwent successful left bundle branch-optimized cardiac resynchronization therapy. Subsequently, she was diagnosed with type 2 diabetes with a glycated hemoglobin value of 8.4%. Dapagliflozin 10 mg once daily was advised in the morning on day 4. However, the patient experienced AUB in the afternoon, without abdominal pain or discomfort. A gynecological ultrasound showed an endometrial thickness of 2 mm with fluid accumulation within the uterine cavity. We inquired about her medication history again and found that AUB had occurred repeatedly after taking dapagliflozin and resolved upon discontinuation of dapagliflozin. Therefore, we suspected that dapagliflozin may be responsible for this AUB episode, leading to its discontinuation and resulting in resolution of symptoms the next day. Consequently, the patient was discharged from the hospital and followed up via telephone and outpatient review visits. She was advised to administer a reduced dose of dapagliflozin at 5 mg (a half dose of 10 mg) daily. However, she reported continued occurrence of AUB when taking this dosage regimen.

Table 1.

Blood test results.

Variables	Results	Reference range
Hb (g/L)	135	115–150
WBC count (109/L)	8.9	3.5–9.5
Plt count (10×9/L)	240	125–350
Cr (μmol/L)	115	45–84
BUN (mmol/L)	12.1	2.9–8.2
Na (mmol/L)	141	137–147
K (mmol/L)	4.86	3.5-5.3
NT-proBNP (pg/mL)	246	<100
ALT (U/L)	10	7–40
AST (U/L)	17	13–35
ALP (U/L)	57	50–135
Bilirubin (μmol/L)	12.3	0–23
PT (s)	11	9.4–12.5
APPT (s)	33.4	25.1–36.5
INR	0.97	0.87–1.15
Albumin (g/L)	42.9	40–55
Total protein (g/L)	73.6	65–85

Hb, hemoglobin; WBC, white blood cell; Plt, platelet; Cr, creatinine; BUN, blood urea nitrogen; Na, sodium; K, potassium; NT-proBNP, N-terminal pro-brain-type natriuretic peptide; ALT, alanine transaminase; AST, aspartate transaminase; ALP, alkaline phosphatase; PT, prothrombin time; APTT, activated partial thromboplastin time; PT, prothrombin time; INR, international normalized ratio.

Several months later, the patient was readmitted because of the presence of chest tightness and bilateral lower limb edema. Estrogen concentrations were measured and postmenopausal concentrations were found. Moreover, her coagulation function showed no abnormalities. In a recent visit to our hospital, the patient sought medical advice, and we recommended a prescription of 2.5 mg (one quarter of 10 mg) dapagliflozin. Following the administration of this medication, she reported no further incidents of AUB. Subsequently, the patient has been consistently taking this dosage. The patient showed good compliance with this treatment regimen.

The Naranjo scale was used to assess the likelihood of an adverse drug reaction and showed a score of 7 (Table 2). This score indicated a probable relationship between dapagliflozin and the development of AUB in this patient.

Table 2.

The Naranjo scale.

To assess the adverse drug reaction, please answer the following questionnaire and provide the pertinent score
		Yes	No	Do not know	Score
1.	Are there previous conclusive reports on this reaction?		0
2.	Did the adverse event appear after the suspected drug was administered?	+2
3.	Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered?	+1
4.	Did the adverse reaction reappear when the drug was readministered?	+2
5.	Are there alternative causes (other than the drug) that could have caused the reaction?	−1
6.	Did the reaction reappear when a placebo was provided?			0
7.	Was the drug detected in the blood (or other fluids) in concentrations known to be toxic?			0
8.	Was the reaction more severe when the dose was increased, or less severe when the dose was decreased?	+1
9.	Did the patient have a similar reaction to the same or similar drugs in any previous exposure?	+1
10.	Was the adverse event confirmed by any objective evidence?	+1
Total score					7

Different point values (−1, 0, +1, or +2) are assigned to each answer.

Total scores range from −4 to +13. A reaction is considered definite if the score is ≥9, probable if 5 to 8, possible if 1 to 4, and doubtful if ≤0.

Discussion

SGLT2 inhibitors are a class of drugs that were initially developed as antidiabetic agents for their antihyperglycemic effects.^6,7 However, large-scale trials have demonstrated that SGLT2 inhibitors improve cardiovascular outcomes in patients with heart failure and reduced ejection fraction.^8,9 On the basis of these trials, the guidelines recommend the use of SGLT2 inhibitors for treating patients with heart failure and reduced ejection fraction. ¹⁰ Dapagliflozin, which is a selective SGLT2 inhibitor, was an appropriate treatment option for our patient with dilated cardiomyopathy and heart failure and reduced ejection fraction.

No gynecological tumors were detected by an ultrasound examination in our patient. Inquiring about her medication history showed that she experienced repeated episodes of AUB after taking dapagliflozin. AUB is defined as excessive or irregular uterine bleeding outside normal prolonged menstrual bleeding or postmenopausal bleeding. ¹¹ Various factors can contribute to AUB, such as physiological changes, pharmacological effects, and pathological conditions (e.g., gynecological tumors, coagulation dysfunction, and endocrine abnormalities).

The Naranjo scale was developed to help standardize assessment of causality for all adverse drug reactions by Naranjo and coworkers. ¹² This scale consists of 10 questions that are answered as “Yes,” “No,” or “Do not know.” Different point values (−1, 0, +1, or +2) are assigned to each answer. Total scores range from −4 to +13. A reaction is considered definite if the score is ≥9, probable if 5 to 8, possible if 1 to 4, and doubtful if ≤0. A score of 7 indicated a probable relationship between dapagliflozin and the development of AUB in our patient. In addition, the patient reported receiving anti-heart failure medications (including furosemide, spironolactone, metoprolol, sacubitril/valsartan, and dapagliflozin) for many years. After experiencing AUB from the use of medication, attempts were made to stop each medication one by one. Eventually, we found that the bleeding was related to the use of dapagliflozin.

We conducted a literature review of PubMed and Cochrane databases from their earliest available dates until 28 February 2024 to identify any English-language studies reporting AUB as an outcome or adverse effect of SGLT2 inhibitors. No case reports were found that reported SGLT2 inhibitors contributing to the development of AUB. However, the VigiAccess database reported 34 cases of vaginal hemorrhage when using dapagliflozin. The mechanism underlying abnormal AUB caused by dapagliflozin remains unclear. SGLT-2 inhibitors can reduce platelet aggregation, intracellular calcium mobilization, thromboxane B2 concentrations, and PAC-1 and Akt expression, and this response is potentiated by nitric oxide +prostacyclin. ¹³ Similarly, a study reported that dapagliflozin decreased activated CD62P-positive platelets in Ldlr−/− mice fed a diabetogenic diet without affecting the bleeding time and further reduced endogenous thrombin generation, thereby decreasing one of the most important platelet activators. ¹⁴ In addition, a direct inhibitory effect of dapagliflozin on isolated platelets was observed. Furthermore, dapagliflozin lowers CD62P-positive platelet counts in humans after stimulation with collagen-related peptide or thrombin receptor activator peptide-6 without affecting hemostasis. ¹⁵ These reports suggest that dapagliflozin reduces platelet activation. However, we only measured the platelet count and did not test platelet function in our patient. Moreover, the average lifespan of platelets is 7 to 10 days in humans. ¹⁶ The resolution of bleeding took approximately 30 hours in our patient, which suggests that this hypothesized mechanism of AUB by dapagliflozin is unlikely. In addition, previous studies have reported that the baseline estimated glomerular filtration rate, glycemia, and body weight affect the pharmacokinetics of dapagliflozin.^17,18 Further research is required to investigate the potential mechanisms of AUB by dapagliflozin.

This case report has several limitations. First, estrogen concentrations were measured several months later and not at the time when AUB occurred after taking dapagliflozin. Therefore, we cannot establish a direct relationship between estrogen concentrations and the occurrence of AUB. Second, the patient’s refusal to undergo an endometrial biopsy resulted in uncertainty whether the AUB was caused by uterine disease. Third, we only tested the platelet count without testing the platelet function. We cannot exclude the possibility of platelet dysfunction. Fourth, the patient’s description of the bleeding volume was subjective and not easily quantifiable. Assessing whether there was a dose-response relationship between the dosage and the volume of bleeding was not possible. However, when the patient took 2.5 mg dapagliflozin, no further incidents of AUB were reported.

In conclusion, the exact mechanism underlying AUB caused by dapagliflozin currently remains unclear. Physicians should remain vigilant regarding hemorrhagic diseases such as AUB.

Supplemental Material

sj-pdf-1-imr-10.1177_03000605241271750 - Supplemental material for Dapagliflozin-induced abnormal uterine bleeding in a patient with dilated cardiomyopathy and chronic heart failure: a case report

Supplemental material, sj-pdf-1-imr-10.1177_03000605241271750 for Dapagliflozin-induced abnormal uterine bleeding in a patient with dilated cardiomyopathy and chronic heart failure: a case report by Shikun Gong, Shunan Zhang, Yun Ye and Meiling Wu in Journal of International Medical Research