SERTRALINE-INDUCED HYPOGLYCEMIA IN TYPE 2 DIABETES PATIENTS

Case Report SERTRALINE-INDUCED HYPOGLYCEMIA IN TYPE 2 DIABETES PATIENTS David Ni, MD 1 ; Shikha G. Khosla, MD 2 ; Eric S. Nylen, MD 2 ABSTRACT Objective: To report the clinical outcomes of 2 type 2 diabetes patients admitted for severe and precipitous hypoglycemia after initiation of sertraline and subsequent resolution after discontinuation of the medication. Methods: Case reports with literature review. Results: Case 1: A 58-year-old African American man with poorly controlled type 2 diabetes was admitted for unresponsiveness due to severe hypoglycemia. Twelve days prior to admission, he was started on sertraline and observed declining fasting blood sugar levels, with 2 episodes of symptomatic hypoglycemia. Despite discontinuation of insulin for 48 hours during admission, resolution of hypoglycemia only occurred after discontinuation of the sertraline. Despite titration of insulin to pre-admission dosage following discharge, he was re-admitted shortly for hyperosmolar hyperglycemic state. Case 2: An 85-year-old Caucasian man with well-controlled type 2 diabetes was admitted for 3 episodes of hypoglycemia in 1 day. At home, he was on metformin and pioglitazone for his diabetes. He was started on sertraline 2 months prior, with progressively decreasing Submitted for publication January 12, 2015 Accepted for publication March 19, 2015 From the 1 Section of Endocrinology, Temple University School of Medicine, Philadelphia, Pennsylvania, and 2 Division of Endocrinology, Veterans Affairs Medical Center, Washington, DC, and George Washington University, Washington, DC. Address correspondence to Dr. David Ni, 10710 Charter Drive, Suite 410, Columbia, MD 21044. E-mail: dnister@gmail.com DOI: 10.4158/EP15616.CR To purchase reprints of this article, please visit: www.aace.com/reprints. Copyright 2016 AACE. fasting glucose levels. After discontinuation of the sertraline on the second day of his admission, there were no further recurrences of hypoglycemia. Conclusion: These cases demonstrate through temporal correlation that sertraline may be associated with hypoglycemia in conjunction with antidiabetic agents. Although this potential side effect is rarely reported and not mechanistically defined, sertraline and other selective serotonin re-uptake inhibitors should be considered as possible etiologies when evaluating severe recurrent hypoglycemia. (AACE Clinical Case Rep. 2016;2:e15-e19) Abbreviations: egfr = estimated glomerular filtration rate; SSRI = selective serotonin re-uptake inhibitor INTRODUCTION The prevalence of depression co-occurring with diabetes is estimated to be 27% (1); some studies have found that the risk of depression is doubled as compared to the general population (2). Selective serotonin re-uptake inhibitors (SSRIs) such as sertraline are commonly prescribed, given their effectiveness and favorable pharmacologic profile. Although hypoglycemia is listed as a serious side effect (3), there is a paucity of published cases reported in humans. Experiments using mouse models have yielded mixed results in the past (4). We present 2 possible cases of sertraline-associated hypoglycemia in diabetic patients. CASE REPORT Case 1 A 58-year-old African American man with uncontrolled type 2 diabetes mellitus (T2DM) (hemoglobin A 1c [HbA 1c ] 1 month prior to admission, >14%), normal renal func- Copyright 2016 AACE AACE CLINICAL CASE REPORTS Vol 2 No. 1 Winter 2016 e15

e16 Sertraline-Induced Hypoglycemia, AACE Clinical Case Rep. 2016;2(No. 1) tion (creatinine, 1.0 mg/dl; estimated glomerular filtration rate [egfr], 95 ml/min/1.73 m 2 ), and normal liver function (albumin, 3.3 g/dl; aspartate transaminase [AST], 31 U/L; alanine transaminase [ALT], 31 U/L) was admitted for symptomatic hypoglycemia. The patient denied any past history of hypoglycemia or potential causes of adrenal insufficiency. One month prior to admission, his capillary blood glucose averaged 200 mg/dl on a diabetes regimen comprised of insulin glargine 50 units daily and 20 units at bedtime, insulin aspart 10 units before dinner, and metformin 500 mg twice daily. He was started on sertraline 25 mg daily 12 days prior to admission, which was later increased to 50 mg daily 5 days prior to admission. With no other medications reported, he observed decreased insulin requirements, with fasting blood glucose significantly lower, at 80 mg/dl, despite his usual diet and activity level. He also experienced 2 episodes of mild, nocturnal hypoglycemia prior to hospitalization. The night before admission, the patient skipped dinner and only administered 20 units of insulin glargine. The next morning, emergency medical services were called for symptomatic hypoglycemia; he had a capillary glucose of 35 mg/ dl, which responded to dextrose 50% in water (D50W). His C-peptide level was noted to be 0.21 ng/ml (reference range, 0.8 to 3.1 ng/ml), and his insulin level was 41 μiu/ ml (reference range, <17 μiu/ml). Despite holding diabetic medications on admission, hypoglycemia recurred overnight, with a decrease of blood sugar from 117 to 34 mg/dl. On the second day, his fasting serum glucose was 61 mg/dl, which later rose to 176 mg/dl at lunch and 199 mg/dl at dinner. Hypoglycemia precipitously re-occurred, with a drop in glucose to 52 mg/ dl that evening. With no other scheduled medications aside from sertraline, the SSRI was discontinued on the third day with resolution of hypoglycemia; his fasting serum glucose was 142 mg/dl on the fourth day and 209 mg/dl on the fifth day. Subsequently, he was discharged on metformin 500 mg twice a day along with 50% of his morning dose of insulin glargine. One week later, his fasting glucose ranged between 127 and 253 mg/dl; 2 weeks afterwards, he was noted to have an HbA 1c of 13.8%, with persistent fasting hyperglycemia between 244 and 400 mg/dl (Table 1 and Fig. 1). Despite continuation of metformin and titration of insulin to his preadmission regimen of 50 units in the morning and 20 units at bedtime, he was admitted shortly thereafter for hyperosmolar hyperglycemic state (HHS). Case 2 An 85-year-old Caucasian man with well-controlled T2DM (recent HbA 1c, 5.5%), stage III chronic kidney disease (creatinine, 1.25 mg/dl; egfr, 52 ml/min/1.73 m 2 ), and normal liver function tests (albumin, 2.5 g/dl; alkaline phosphatase, 120 U/L; ALT, 19 U/L; AST, 31 U/L) was admitted for severe hypoglycemia. The patient had been started on sertraline 50 mg daily 2 months prior to hospitalization. At baseline, his fasting capillary glucose range was 115 to 140 mg/dl. After initiation of sertraline, the range further decreased to 85 to 100 mg/dl. Despite instructions to discontinue, the patient continued both metformin and pioglitazone. On the morning of admission, the patient was noted to be combative, with seizure-like symptoms. Emergency medical services recorded a capillary glucose of 40 mg/dl, which responded to D50W administration. Despite adequate food intake, he was combative again, with a capillary blood glucose measurement of 36 mg/dl, improving to 162 mg/ dl after intramuscular glucagon administration. Despite consumption of food and juice in the emergency room, his blood sugar precipitously dropped to 35 mg/dl. C-peptide and insulin levels were not obtained, but despite intervention with dextrose 10% drip overnight and glucagon 1 mg intramuscularly every 8 hours, his blood sugars were no higher than 85 mg/dl. On the second day of admission, sertraline and the dextrose 10% drip were discontinued, with blood glucose ranging between 71 and 115 mg/dl. On the third day of admission, blood glucoses ranged between 89 and 195 mg/ dl (Table 2 and Fig. 2). For the remainder of the patient s stay, his blood sugars progressively rose, with no recurrences of hypoglycemia. DISCUSSION These 2 cases underscore the importance of medication review when evaluating hypoglycemia and further suggest Table 1 Capillary Blood Glucose (mg/dl) for Case 1 Date Medication Breakfast Lunch Dinner Bedtime April 21 Sertraline 50 mg 35 117 34 April 22 Sertraline 50 mg 180/61 176 199 52 April 23 Sertraline stopped 78 227 170 April 24 Lantus 25 units SQ am 142 154 134 April 25 209 176 Abbreviation: SQ = subcutaneous.

Sertraline-Induced Hypoglycemia, AACE Clinical Case Rep. 2016;2(No. 1) e17 Fig. 1. Capillary blood glucose levels for case 1. Corresponding times at which capillary blood glucose levels are checked for breakfast, lunch, dinner, and bedtime are 7:00 am, 12 noon, 5:30 pm, and 9:30 pm, respectively, unless otherwise specified. Table 2 Capillary Blood Glucose (mg/dl) for Case 2 Date Medication Breakfast Lunch Dinner Bedtime November 27 Sertraline 50 mg 36 40/162/35 36/60 November 28 Sertraline 50 mg; stopped thereafter 85 104 109 165 November 29 71 96 112 115 November 30 89 108 157 195 December 1 95 147 153 206 Fig. 2. Capillary blood glucose levels for case 2. Corresponding times at which capillary blood glucose levels are checked for breakfast, lunch, dinner, and bedtime are 7:00 am, 12 noon, 5:30 pm, and 9:30 pm, respectively, unless otherwise specified.

e18 Sertraline-Induced Hypoglycemia, AACE Clinical Case Rep. 2016;2(No. 1) that sertraline may be a contributor. In the first case, the kinetics and time course of initiation as well as discontinuation of sertraline suggest a contribution to the proximal cause of hypoglycemia. Although the insulin level may reflect exogenous administration, the patient was re-admitted for HHS within 1 month, despite resuming his pre-admission insulin and metformin regimen, with sertraline discontinuation as the only change. In the second case, the patient only reported taking metformin and pioglitazone. The Lexicomp Drug Interaction Database indicates that there is a Category C risk of interaction between sertraline and pioglitazone (5), whereas metformin is not reported to have any interaction with either. Additionally, metformin is only contraindicated in males with creatinine >1.5 mg/dl; Lipska et al (6) suggest that metformin can be continued with an egfr <60 ml/ min/1.73 m 2 but advise caution for egfr <45 ml/min/1.73 m 2. Although a complete hypoglycemia work-up (insulin, C-peptide, and proinsulin) was not obtained, metformin and pioglitazone appear less likely to precipitate hypoglycemia based on current prescribing guidelines. In both cases, obtaining a sertraline level would have been helpful in addition to a cautious rechallenge with the suspected agent. Sulfonylurea screens were not obtained given low index of suspicion, but metformin levels may have further clarified the hypoglycemia etiology. A literature search of the PubMed and Ovid databases yielded only 1 letter to the editor and 2 published case reports of hypoglycemia with sertraline in humans. Pollak et al (7) reported the case of a nondiabetic patient with hypoglycemia unresponsive to juice and glucagon. The suspected mechanism of action was increased serotonin concentrations, resulting in increased serum insulin concentrations and impaired gluconeogenesis. Takhar and Williamson (8) reported a diabetic patient on sulfonylurea and sertraline who developed hypoglycemia, in which the mechanism was thought to be decreased sulfonylurea clearance from SSRImediated inhibition of cytochrome P450. A letter to the editor described a patient with type 1 diabetes having 3 episodes of difficult-to-treat hypoglycemia after initiating sertraline 50 mg daily. There were no recurrences for at least 2 years after discontinuation of the sertraline. The author s investigation revealed more than 440 reports of hypoglycemia concurrent with SSRI treatment in the World Health Organization register and more than 100 involving sertraline (9). Additionally, there have been reports of hypoglycemia unawareness on initiation of SSRIs in diabetic patients and resolution with their discontinuation (10). In a study by Gomez et al (11) in 2001, Wistar rats premedicated with sertraline were shown to neutralize hyperglycemia after a glucose load. In that study, the same results were replicated in nondiabetic and streptazocin-induced diabetes rat models (11). In a study by Erenmemisoglu et al (12), sertraline and fluoxetine both reduced plasma glucose independent of insulin levels in normoglycemic and alloxaninduced hyperglycemic mice. Two other mouse studies suggest that serotonin can also induce hypoglycemia as mediated by 5-hydroxytryptamine 1 and 5-hydroxytryptamine 2 receptors by modifying the release of insulin, whereas antagonism of the receptors impaired insulin elevation (13,14). Another mouse study also demonstrated that sertraline enhances insulin release in both the fasting and glucose overload states (15). Pinacidil, a potassium channel opener, has also been shown in vivo and in vitro to antagonize the hypoglycemic effects of sertraline in the same species of rat, suggesting that sertraline may potentially cause hypoglycemia through potassium channel closure in in pancreatic β-cells, resulting in release of insulin (16). Conversely, sertraline has also been demonstrated to augment counterregulatory responses to hypoglycemia in rats. Sanders et al (17) showed elevated epinephrine, norepinephrine, and glucagon levels in rats treated with sertraline. CONCLUSION Sertraline product labels list hypoglycemia as a rare adverse effect, and there appear to be only 3 case reports published in the literature. Although the exact mechanism of hypoglycemia is not clear, animal models demonstrate decreased fasting glucose and impaired postprandial hyperglycemia with sertraline administration. This suggests that glycemic improvement may be a result of 5-hydroxytryptamine receptor activation or inhibition of potassium channels, resulting in insulin release. Given the common prescription of sertraline in diabetic patients and the potential severity of hypoglycemia, SSRI usage should be considered when assessing factitious or medication-induced hypoglycemia, particularly when other diabetic medications are concurrently used. A database review to determine whether sertraline initiation empirically lowers glucose or reduces diabetic medication doses in patients would further clarify causality and potentially lead to further investigation into possible mechanisms in humans. DISCLOSURE Doctors Khosla and Nylen have no multiplicity of interest to disclose. Doctor Ni owns public stock in Abbvie, Abbott Laboratories, Bristol Myers Squibb, GlaxoSmithKline, Merck, Novartis, Novo Nordisk, Pfizer, Sanofi, and Stryker Corp. REFERENCES 1. Centers for Disease Control and Prevention. Mental health and chronic diseases CDC fact sheet. Available at: http://www.cdc.gov/nationalhealthyworksite/docs/ issue-brief-no-2-mental-health-and-chronic-disease.pdf. Accessed October 7, 2015.

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