Drug-Induced Glucose Alterations Part 1: Drug-Induced Hypoglycemia Mays H

Pharmacy and Therapeutics

Drug-Induced Glucose Alterations Part 1: Drug-Induced Hypoglycemia Mays H. Vue, PharmD, and Stephen M. Setter, PharmD, CDE, CGP

Many pharmacological agents com- on Hypoglycemia has defined and monly used in clinical practice affect classified hypoglycemia based on glucose homeostasis, interfering with the severity of symptoms in patients the body’s balance between insulin, diagnosed with diabetes as outlined glucagon, catecholamines, growth in Table 2.2 In general, severe hypo- hormone, and cortisol. Drug-induced glycemia develops when a reduction serum glucose alterations manifested in blood glucose is enough to require as hyperglycemia or hypoglycemia assistance from another person and ranging from mild to moderate to actively administer carbohy- to severe symptoms either appearing drate, glucagon, or other corrective acutely or chronically, have perpetual actions.2 Severe hypoglycemia is effects on the body, particularly in a serious clinical syndrome that patients with diabetes. This article continues to be the most common and a second one that will appear in endocrine emergency faced by health the next issue of this journal review care providers and remains the drug-induced serum glucose altera- limiting factor in effective diabetes tions in a two-part series. In this management for many patients.6 article, we review pertinent clini- Hypoglycemia has been associ- cal information on the incidence of ated with a higher number of hospital drug-induced hypoglycemia and admissions, longer hospital stays, and discuss the underlying pathophysi- significant morbidity and mortality ological mechanisms involved. in patients with diabetes or hypergly- Hypoglycemia is clinically cemia.6,7 In a systemic review of 448 defined as a serum glucose con- publications describing drug-induced centration low enough to cause the hypoglycemia,8 90% of reported signs and symptoms differentiated in cases were classified as severe hypo- Table 1.1–4 Depending on the sever- glycemia in which symptoms were ity, hypoglycemic symptoms include present and required assistance by irritability, impaired concentration, someone other than the patient. neurological deficits, seizures, coma, Although hypoglycemia can be and even neuronal death.5 However, iatrogenic, in which normal body clinical manifestations vary from defenses are impaired, treatment individual to individual, and some with insulin or insulin secretagogues report hypoglycemic symptoms even (e.g., sulfonylureas [SUs] and meg- when serum glucose levels do not litinides), as monotherapy or in reflect hypoglycemia or vice versa. combination, account for a majority Although definitions of hypogly- of hypoglycemic events.3 In addition cemia differ in the literature, many to glucose-lowering agents, many trials will differentiate between commonly used non-antidiabetic hypoglycemia (asymptomatic and drugs have been reported to cause or symptomatic low serum glucose contribute to drug-induced hypogly- levels) and severe hypoglycemia. This cemia, even in individuals without article will cover and report both diabetes. Furthermore, as people when applicable. age and their number of comorbidi- The American Diabetes ties and medications increase over Association (ADA) Workgroup time, they expose themselves to an Diabetes Spectrum Volume 24, Number 3, 2011 171 Pharmacy and Therapeutics

Table 1. Signs and Symptoms of Hypoglycemia3,4 Signs Symptoms Diaphoresis Neurogenic (Autonomic) Neuroglycopenic Pallor Catecholamine-mediated Acetylcholine-mediated Cognitive impairment Increased heart rate (adrenergic) (cholinergic) Behavioral changes Elevated systolic blood Irritability pressure Tremor Sweating Drowsiness Palpitations Hunger Blurred vision Anxiety/arousal Tingling Difficulty with speech Trembling Confusion Feeling faint Seizure Coma

Table 2. ADA Workgroup on Hypoglycemia Definition and Classification of Hypoglycemia in People With Diabetes1,2 Type of Hypoglycemia Presentation of Symptoms Severe hypoglycemia An event requiring assistance of another person to actively administer resuscitative actions Documented symptomatic hypoglycemia An event during which typical symptoms of hypoglycemia are accompanied by a measured plasma glucose concentration ≤ 70 mg/dl Asymptomatic hypoglycemia An event not accompanied by typical symptoms of hypoglycemia but with a measured plasma glucose concentration ≤ 70 mg/dl Probable symptomatic hypoglycemia An event during which symptoms typical of hypoglycemia are not accompanied by a plasma glucose determination (but that was pre- sumably caused by a plasma glucose concentration of ≤ 70 mg/dl) Relative hypoglycemia An event during which the person with diabetes reports any of the typical symptoms of hypoglycemia and interprets those as indica- tive of hypoglycemia, with a measured plasma glucose concentration > 70 mg/dl but approaching the hypoglycemic level exponential risk for possible drug in the management of diabetes will used in the management of diabetes. interactions or cumulative adverse allow for more practical and safe Although numerous drugs can lower effects that may result in asymptom- health care practices. serum glucose concentrations, this atic or symptomatic hypoglycemia. Medications commonly used for article will review non-antidiabetic Thus, thoroughly reviewing a diabetes treatment are not discussed drugs or drug classes associated with patient’s medication history is in detail in this review because hypoglycemia used in patients with essential, and drug-associated causes hypoglycemia has been well estab- diabetes (Table 4). should always be included in the dif- lished with the use of insulin, SUs, ferential diagnosis of hypoglycemia and meglitinides as monotherapy or ACE Inhibitors until ruled out by other causes (e.g., in combination with other agents In 1985, the first case of ACE non-endocrine disease, trauma, or such as metformin, thiazolidinedio- inhibitor–induced hypoglycemia infections). nes (TZDs), exenatide, or dipeptidyl was reported with the administra- Serum glucose reductions sec- peptidase-4 (DPP-4) inhibitors. tion of captopril.11 Since then, several ondary to pharmacological agents However, metformin, TZDs, and reports and small studies have pub- are caused by multiple actions that α-glucosidase inhibitors such as lished the incidence of hypoglycemia include pharmacokinetic or phar- acarbose and miglitol, when admin- associated with ACE inhibitor use, macodynamic drug interactions istered as monotherapy at usual but the data remain controversial. or additive hypoglycemic effects doses, should have little to no risk In a small case-control study from polypharmacy. Recognition of of hypoglycemia based on their from the Netherlands,12 94 patients underlying pathophysiological mech- mechanisms of action. As a point were identified and admitted to the anisms responsible for drug-induced of reference, Table 39,10 provides the hospital with hypoglycemia, and hypoglycemia from pharmacological absolute risk of hypoglycemia for 654 control subjects were selected treatments other than those used common glucose-lowering agents from the same cohort. As many as 172 Diabetes Spectrum Volume 24, Number 3, 2011 Pharmacy and Therapeutics

Table 3. Absolute Risk of Mild-to-Moderate Hypoglycemia With Commonly Used Glucose-Lowering Agents9,10 Drug Class Drug Monotherapy Combination Therapy Biguanides MET † See combinations See combinations with MET below. with MET below. Second-generation Glimepiride 0.9–1.7% + pioglitazone 13.4–15.7% sulfonylureas (SUs) + rosiglitazone 3.6–5.5% Glipizide 3% + MET 7.6–12.6% Glyburide 21.3% + MET 11.4–37.7% Meglitinides Nateglinide 1.3–3% * * Repaglinide 16–31% + MET 33% Glucagon-like pep- Exenatide 4.5–35.7% + MET 4.5–5.3% tide-1 (GLP-1) + SU 14.4–35.7% + MET + SU 19.2–27.8% + TZD 11% Liraglutide 9.7% + MET 3.6% + glimepiride 7.9% + MET + glimepiride 27.4% Thiazolidinediones Pioglitazone † + MET 4.4% (TZDs) + SU 26.7–28.8% + insulin 53.4–56.4% Rosiglitazone † + MET 3.6–5.5% + glimepiride 3.6–5.5%

α-Glucosidase Acarbose † + SU or insulin 2% inhibitors Miglitol † * * DPP-4 inhibitors Sitagliptin 0.6–12.2% + MET 1.6% + glimepiride 12.2% +/- MET Saxagliptin 2.7–14.6% + MET 3.4–7.8% + glyburide 13.3–14.6% + TZD 2.7–4.1% Amylinomimetic Pramlintide 16.8% * * MET, metformin; SU, sulfonylurea; TZD, thiazolidinedione. *Risk not reported. †Absolute risk data are not available because these agents cause little to no risk of hypoglycemia when used in monotherapy and within normal dosing ranges. Although hypoglycemia risk is low in monotherapy, when given in combination with oral hypoglycemic agents or insulin, additive effects increase the risk of hypoglycemia, as shown above.

13.8% of all hospital admissions three- to fourfold increased risk of ulating hepatic glucose production. for hypoglycemia were significantly hypoglycemia. Although the exact Suppression of peripheral sympa- attributable to the use of ACE mechanism for its glucose-lowering thomimetic overactivity may also be inhibitors (odds ratio 2.8 [95% effects is unknown, the hypoth- involved in blood glucose–lowering CI 1.4–5.7]), but this was among esis involves an indirect increase in effects of ACE inhibitors.14 patients with diabetes concomitantly insulin sensitivity by increasing cir- treated with insulin or oral antidia- culating kinine, which in turn leads Alcohol/Ethanol betic agents for at least 1 year. to vasodilatation in the muscles and Hypoglycemia associated with Another small study13 determined ultimately increased glucose uptake alcohol ingestion is a well-established that ACE inhibitor use in people in muscle tissue. Bradykinin may also problem in patients with diabetes. with diabetes was associated with a have a contributory role in downreg- Patients who are treated with anti- Diabetes Spectrum Volume 24, Number 3, 2011 173 Pharmacy and Therapeutics

Table 4. Non-Diabetes Drugs Associated With Hypoglycemia1,3,9,17,20 Drug Class Drug Mechanism of Glucose- Common Indications Clinical Lowering Effects Significance ACE inhibitors • Benazepril Indirectly increases insulin Hypertension, conges- + • Enalapril sensitivity by increasing tive heart failure (CHF), • Lisinopril circulating kinins, which diabetic nephropathy, • Perindopril leads to vasodilatation in the post-myocardial infarc- • Ramipril muscles and increased glu- tion (MI) • Captopril cose uptake in muscle tissue • Fosinopril • Moexipril • Quinapril • Trandolapril β-Blockers Noncardioselective: Inhibits glycogenolysis; atten- Post-MI, chronic angina + • Levobunolol uates signs and symptoms pectoris/coronary artery • Metipranolol disease, hyperten- • Nadolol sion, acute coronary • Propranolol syndromes, CHF, • Sotalol perioperative prevention • Timolol of cardiac events, acute myocardial infarction Cardioselective: • Acebutolol • Atenolol • Betaxolol • Bisoprolol • Esmolol • Nebivolol • Metoprolol Chloramphenicol May inhibit the metabolism Bacterial meningitis, + of SUs cystic fibrosis, salmonella infection, typhoid fever, acne Chloroquine Unknown Malaria, hemophago- + cytic syndrome, porphyria cutanea tarda, sarcoidosis, ulcerative colitis Clofibrate Enhances the effect of SUs Acne, diabetes insipidus, + glaucoma, hyperlipid- emia, migraine, multiple sclerosis, prophylaxis for MI, neonatal jaundice Disopyramide Unknown; appears to result Ventricular arrhythmia ++ from endogenous insulin secretion Ethanol Impairs gluconeogenesis; +++ increases insulin secretion continued on p. 175

diabetic agents such as insulin and The proposed mechanism of tion.16 Alcohol may also indirectly SUs (e.g., glyburide) are at higher alcohol-induced hypoglycemia in increase endogenous insulin secre- risk for developing hypoglycemia, a fasting and intoxicated patient is tion, contributing to hypoglycemic particularly those who have been primarily the inhibition of gluconeo- effects observed in individuals.17 previously fasting or who have a his- genesis along with depleted glycogen Furthermore, symptoms of hypogly- tory of chronic abuse.15 stores as a response from starva- cemia can bear such a resemblance 174 Diabetes Spectrum Volume 24, Number 3, 2011 Pharmacy and Therapeutics

Table 4: Non-DiabetesTable 4. Non-Diabetes Drugs Associated Drugs Associated With Hypoglycemia With Hypoglycemia1,3,9,17,20, continued1,3,9,17,20 from p. 174 Quinolones • Ciprofloxacin Unknown; enhanced insulin Bacterial conjunctivitis, + (Fluoroquinolone) • Gatifloxacin secretion appears to result bronchitis, community- • Levofloxacin from blockade of ATP- acquired pneumonia, • Moxifloxacin sensitive potassium channels gonorrhea, uncompli- • Norfloxacin in pancreatic β-cells cated skin infections, • Ofloxacin pyelonephritis, acute sinusitis, urinary tract infections Pentamidine Cytolytic release of insulin Pneumocystis +++ pneumonia, cutane- ous leishmaniasis, trypanosomiasis, visceral leishmaniasis Salicylates • Aminosalicylic Increases insulin secretion Pain, fever, inflamma- + acid and sensitivity; may alter tion, cerebrovascular • Aspirin pharmacokinetic disposition accident, MI • Choline magne- of SUs sium trisalicylate • Magnesium salicylate • Salsalate + Low probability of occurrence and/or low level of drug-induced hypoglycemia expected in patients. ++ Moderate-to-high probability of occurrence but degree of drug-induced hypoglycemia may or may not be clinically significant. +++ High probability of occurrence; drug-induced hypoglycemia is clinically significant. to symptoms of mild alcohol intoxi- hypoglycemia. The catecholamine- insulin.21 Over time, patients become cation that patients may be negligent mediated neurogenic hypoglycemic increasingly deficient in insulin as the of the differences. Patients should be symptoms masked by this class pancreatic destruction progresses, appropriately cautioned about close of medications include tremor eventually resulting in hyperglycemic monitoring of blood glucose levels to and palpitations. Hunger, tremor, episodes. Within a matter of weeks ensure the actual cause.15,17 irritability, and confusion may be to months, this consequential adverse concealed as well. Sweating, how- effect can lead to the development of β-blockers ever, remains unmasked and may be new-onset diabetes.9,17,20 β-blockers can cause or exacerbate the only recognizable sign of hypo- hypoglycemia in some individu- glycemia in individuals treated with Quinolone (Fluoroquinolone) als, either by worsening an already β-blockers.17,20 Antibiotics present hypoglycemic episode Quinolones, commonly known as or by delaying recovery time.17 Pentamidine fluoroquinolones, are widely used as The mechanism responsible for Pentamidine is used in the treatment broad-spectrum antibiotics against β-blocker–induced hypoglycemia of opportunistic infections associated community- and health care–asso- involves inhibition of hepatic glucose with immunosuppression such as ciated infections. Incidences of production, which is promoted by Pneumocystis pneumonia, although quinolone-induced hypoglycemia in sympathetic nervous stimulation. In it is no longer considered a first-line the literature vary within the class, addition, adrenergic counterregula- therapy because of its glucose-alter- but gatifloxacin has been associ- tion is diminished, resulting in a ing adverse effects.9 Hypoglycemia is ated with having a greater effect on reduction in glycogenolysis.17,18 the most common metabolic abnor- increasing insulin levels and reduc- Non-cardioselective β-blockers mality observed within 5–14 days ing blood glucose compared to other such as propranolol are more likely of initiating therapy and occurs in quinolones.1 In fact, the prescrib- to cause hypoglycemia than cardio- about 6–40% of patients.17,20 ing information for gatifloxacin selective ones such as atenolol and Pentamidine-induced hypogly- specifically states that diabetes is metoprolol. Nevertheless, patients cemia is caused by an increase in a contraindication for use.22 The on the latter should still be cautioned insulin secretion via a cytolytic prescribing information for other about the potential for drug-induced response in the pancreas. Intravenous quinolones (e.g., ciprofloxacin, levo- hypoglycemia.19 glucose or oral diazoxide at initiation floxacin, and moxifloxacin) include Furthermore, β-blockers have the of therapy is often given in antici- information about altering serum potential for masking symptoms of pation of this cytolytic release of glucose levels but only suggest cau- Diabetes Spectrum Volume 24, Number 3, 2011 175 Pharmacy and Therapeutics

tion regarding their use in patients weeks, A1C was lowered by ≥ 0.5% 3Dipiro JT, Talbert RL, Yee GC, Matzke with diabetes. from baseline (P = 0.009). Patients GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach. 6th ed. The mechanism is unknown, but were concomitantly treated with diet Stamford, Conn., Appleton & Lange, 2005 it has been theorized that quino- and exercise alone, an insulin secre- 4 lones indirectly cause hypoglycemia tagogue, or a DPP-4 inhibitor, either de Galen BE, Schouwenberg BJJW, Tack CJ, Smits P: Pathophysiology and management through blockade of adenosine 5′tri- as monotherapy or in combination. of recurrent hypoglycemia and hypoglyce- phosphate (ATP)-sensitive potassium Other studies have shown high-dose mic unawareness in diabetes. Neth J Med channels in the pancreatic β-cells aspirin therapy (e.g., 4–7 g/day) to 64:269–279, 2006 that regulate calcium influx. 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Nonetheless, the potential Wang X, Li H: Association between admis- elderly.1,24 Although incidences of for salicylate-induced hypoglycemia sion hypoglycemia and in-hospital and 3 year quinolone-induced hypoglycemia mortality in older patients with acute myocar- should be considered in patients, dial infarction. Heart 96:1444–1450, 2010 have mostly been reported in older particularly those administered high 8 adults with diabetes concomitantly doses or taking concurrent insulin or Murad MH, Coto-Yglesias F, Wang AT, Sheidaee N, Mullan RJ, Elamin MB, Erwin taking insulin or SUs, the adverse oral insulin secretagogues. PJ, Montori VM: Drug-induced hypoglycmia: effect has been reported to develop a systemic review. J Clin Endocrinol Metab in individuals without a history of Summary 94:741–745, 2009 1 Numerous pharmacological agents diabetes. 9Thomson Reuters Healthcare: Micromedex that are commonly used in patients Healthcare Series. 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18Ma RCW, Kong APS, Chan N, Tong PCY, 23Maeda N, Tamagawa T, Niki I, Miura H, Shulman GI: Mechanism by which high-dose Chan JCN: Drug-induced endocrine and Ozawa K, Watanabe G, Nonogaki K, Urmura aspirin improves glucose metabolism in type metabolic disorders. Drug Saf 30:215–245, K, Iguch A: Increase in insulin release by rat 2 diabetes. J Clin Invest 109:1321–1326, 2007 pancreatic islets by quinolone antibiotics. Br 2002 19William-Olsson T, Felleniuis E, Bjorntorp P, J Pharmacol 117:372–376, 1996 Smith U: Differences in metabolic responses 24Greenberg AL, Decerbo M, Fan J: to beta-adrenergic stimulation after pro- Gatifloxacin therapy associated with hypogly- Mays H. Vue, PharmD, is a geri- pranolol or metoprolol administration. Acta cemia. Clin Infect Dis 40:1210–1211, 2005 Med Scand 206:201–206, 1979 atrics resident in the Department 25Williamson RT: On the treatment of 20White JR, Campbell RK: Drug-drug and of Pharmacotherapy and Elder glycosuria and diabetes mellitus with sodium drug-disease interactions and diabetes. Services in the College of Pharmacy Diabetes Educ 21:283–289, 1995 salicylate. BMJ 1:760–762, 1901 26 at Washington State University 21Bouchard P, Sai P, Reach G, Caubarrere I, Goldfine AB, Fonseca V, Jablonski KA, Ganeval D, Assan R: Diabetes mellitus fol- Pyle L, Staten MA, Shoelson SE: The effects in Spokane. Stephen M. Setter, lowing pentamidine-induced hypoglycemia of salsalate on glycemic control in patients PharmD, CDE, CGP, is an associ- in humans. Diabetes 31:40–45, 1982 with type 2 diabetes: a randomized trial. Ann Intern Med 152:346–357, 2010 ate professor in the Department 22Bristol Myers Squibb: Prescribing information for gatifloxacin (Tequin). Princeton, NJ, 27Hundal RS, Petersen KF, Mayerson AB, of Pharmacotherapy at the same 2006 Randhawa PS, Inzucchi S, Shoelson SE, institution.

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