Hydroxychloroquine-Induced Hypoglycemia in a Patient Without Diabetes

Introduction

Hydroxychloroquine is a disease-modifying antirheumatic drug (DMARD) commonly prescribed for the treatment of rheumatic diseases such as Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE). More recently, hydroxychloroquine was used during the early phase of COVID-19 pandemic as a potential treatment. ¹ Hydroxychloroquine-associated hypoglycemia is a rare but well documented adverse effect likely due its effect on altering insulin metabolism by both increasing insulin secretion and inhibiting its clearance. ² In literature, there are several reports of hydroxychloroquine-induced hypoglycemia in diabetic and non-diabetic patients, however, many of these reports have limited follow-up and do not report time to resolution of symptoms.^3-8 In addition, there have been several reports of hypoglycemia in patients treated with shorter courses of hydroxychloroquine for COVID-19 treatment.^9,10 In this case, we report on a patient without diabetes with suspected hydroxychloroquine-induced hypoglycemia with documented time to resolution of symptoms after stopping the offending agent.

Case

A 55 year-old female with a past medical history of hypertension, hypothyroidism, and rheumatoid arthritis (RA) presented to the endocrinology clinic upon referral from her primary care physician to establish specialist care for recurrent hypoglycemic episodes. Per the patient’s account, her fasting blood glucose (BG) was usually 60s-70s mg/dL and post-prandial was 100s mg/dL. When symptomatic, her BG was in the 50s mg/dL. Reported symptoms include nausea, irritability, dizziness, weakness, tremors, mild confusion, and diaphoresis with associated episodes. The patient stated these episodes had been ongoing intermittently for over 30 years and tend to be worsened after eating a high carbohydrate meal. Diagnostic testing after first hypoglycemic episode 30 years ago included an oral glucose tolerance test (OGTT) and a 72-hour fast, all of which were reportedly normal according to the patient. More recently, the patient underwent an adrenocorticotropic hormone (ACTH) stimulation test (normal response >20 mcg/dL) that was normal (cortisol levels: baseline 6.3 mcg/dL--> 30 minutes after 23.2 mcg/dL ---> 60 minutes after 25.4 mcg/dL). Fasting insulin level and C-peptide levels were 21.5 uU/mL (normal range 2.6-24.9 uU/mL) and 4.7 ng/mL (normal range 1.1-4.4 ng/mL), respectively.

Based on patient history, only 2 major changes had occurred in her daily routine, decreasing carbohydrate intake and resuming hydroxychloroquine 200 mg twice daily for her RA. She had previously been on hydroxychloroquine for many years, including while in her 30s, but only resumed taking hydroxychloroquine in the 2 years prior. Based on the limited evidence of possible association of hydroxychloroquine and hypoglycemia, the patient was instructed to hold hydroxychloroquine and follow-up in 4 weeks with the endocrinologist. The plan of care was discussed with the patient’s rheumatologist. At follow-up 4 weeks later, the patient reported continued hypoglycemic episodes. During the visit, a mixed meal test was performed where the patient consumed cereal (approximately 66 g carbohydrates), BG was monitored, and lowest BG reported was 97 mg/dL. Patient was instructed to continue to hold hydroxychloroquine and follow up in 3 months.

After 3 months, the patient reported she had hypoglycemic episodes in the subsequent 3 weeks after the previous visit (7 weeks total holding hydroxychloroquine), but has since remained free of hypoglycemic events. Her lowest BG reading during that span was reported to be 74 mg/dL. In coordination with the rheumatologist’s plan of care, the patient was advised to continue to hold hydroxychloroquine and follow up with her rheumatologist for alternative treatment options as needed. (Figure 1).

OPEN IN VIEWER

Figure 1.

Timeline of patient case.

Discussion

To our knowledge, this is the first case of hydroxychloroquine-induced hypoglycemia with a defined time to resolution of symptoms. There have been several case reports published for non-diabetic patients with hydroxychloroquine-induced hypoglycemia.^3-5 However, there have been other reports of patients with continued symptoms after discontinuation of treatment. Cansu, et al reported that a patient was admitted for hypoglycemia with no other possible etiologies other than hydroxychloroquine use. The patient’s hydroxychloroquine was held and he was discharged; however, he was readmitted 10 days later with continued symptoms of hypoglycemia, including loss of consciousness. ⁶ Other documented cases of hydroxychloroquine-induced hypoglycemia were in patients with underlying diabetes who did not have documented recurrent hypoglycemic symptoms after discontinuation. ⁴ Before determining medication-related hypoglycemia, an assessment of other etiologies of hypoglycemia was performed. Testing centered around various laboratory tests, including ACTH stimulation test, insulin levels, and c-peptide level. ACTH stimulation testing was used to assess for adrenal insufficiency; whereas, insulin and c-peptide levels were collected as a baseline of a mixed meal test to assess for insulin-mediated hypoglycemia. ¹¹ Each of these tests were negative, thus ruling out more common causes of hypoglycemia.

Hydroxychloroquine is associated with complex pharmacokinetics due to its large volume of distribution and long half-life of around 40-50 days. ¹² It is generally regarded that it takes around 5 half-lives for a drug to be roughly 97% eliminated. Therefore, we can hypothesize that it will take around 29 to 36 weeks for hydroxychloroquine to be fully eliminated from the body. Factors, including hepatic dysfunction, can slow the clearance of hydroxychloroquine and renal function may affect clearance to a lesser extent. ¹³ The patient in this case report experienced continued symptoms of hypoglycemia for 7 weeks after discontinuation and did not have any underlying renal or liver dysfunction to our knowledge. Seven weeks is around the single average half-life of hydroxychloroquine and would most likely be approximately 50% eliminated. Although 7 weeks is less than the anticipated amount of time to reach 97% clearance, we hypothesized that prolonged cessation of the medication, greater than 1 half-life, provides adequate decrease in drug concentrations to prompt cessation of symptoms. Further kinetic and clinical studies would be needed to elucidate this finding.

This patient was advised to hold hydroxychloroquine and follow up with her rheumatologist. Hydroxychloroquine was still on hold at the 3-month follow up. Due to cessation of symptoms prior to 50% drug removal, it was recommended for the patient to retrial with hydroxychloroquine 100 mg daily if therapy was to be resumed with hydroxychloroquine.

This case report adds to currently available literature because there is a documented improvement of symptoms after the medication was removed at the 3-month follow up. The Naranjo Adverse Drug Reaction Probability scale indicated a score of 7, which demonstrates a probable relationship between hypoglycemia and hydroxychloroquine exposure. (Table 1) This is consistent with previously reported scores for patients without diabetes with hydroxychloroquine-induced hypoglycemia. ¹⁴ There are some limitations with this case, including the chronicity of symptoms and recent dietary modifications, including reduced carbohydrate intake, that could increase the risk of hypoglycemia. While there is no definite casual relationship established between hydroxychloroquine and the hypoglycemic episodes, it was deemed reasonable to stop therapy to ensure the patient’s safety was the main priority. Given the resolution of the patients hypoglycemic episodes upon prolonged cessation in combination with the probability demonstrated with the Naranjo scale, it is reasonable to conclude the association of hydroxychloroquine-induced hypoglycemia. More studies are needed to elucidate other risk factors that could increase the probability of this drug-related adverse effect.

OPEN IN VIEWER

Table 1.

The Naranjo Adverse Drug Reaction Probability Scale.

Question	Answer	Score
Are there previous conclusive reports on this reaction?	Yes	+1
Did the adverse event appear after the suspected drug was given?	Yes	+2
Did the adverse reaction improve when the drug was discontinued or a specific antagonist was given?	Yes	+1
Did the adverse reaction appear when the drug was readministered?	Not done	0
Are there alternative causes that could have caused the reaction?	No	+2
Did the reaction reappear when a placebo was given?	Not done	0
Was the drug detected in any body fluid in toxic concentrations?	Not done	0
Was the reaction more severe when the dose was increased, or less severe when the dose was decreased?	Not done	0
Did the patient have a similar reaction to the same or similar drugs in any previous exposure?	No	0
Was the adverse event confirmed by any objective evidence?	Yes	+1
Total score		7

Conclusion

In conclusion, hydroxychloroquine-induced hypoglycemia is not a novel concept. This case is unique in that it offers a timeline to resolution of symptoms based on relevant pharmacokinetic properties of the medication. Cases of hypoglycemia due to suspected hydroxychloroquine use should be managed with long-term follow up.