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1 April 1993 | Volume 118 Issue 7 | Pages 529-539
Purpose: To review the medications that influence glucose metabolism and to examine the mechanisms of these medications on glucose metabolism.
Data Sources: Data were obtained from a MEDLINE search back to 1966 and included animal and human studies published in the English language.
Study Selection: Approximately 80% of original publications were included after review by the authors. Case reports were included if they provided additional information.
Date Extraction: The original data from the literature were included on the basis of independent extraction by the authors.
Data Synthesis: Many common therapeutic agents influence glucose metabolism. Multiple mechanisms of action on glucose metabolism exist through pancreatic, hepatic, and peripheral effects. Based on circumstances at the time of use, a drug may cause both hyper- and hypoglycemia in a patient. The patient's previous pancreatic reserve, nutritional state, use of other medication, or exposure to alcohol may influence the direction of the plasma glucose alterations.
Conclusion: Hyperinsulinemia and insulin resistance form an intrinsic component of diabetes, hyperlipidemia, and atherosclerotic vascular disease (syndrome X). The induction of hyperinsulinemia and insulin resistance by medication may therefore counteract intended benefits. An extensive review of recent medication in patients with disorders of glucose tolerance and the avoidance of polypharmacy are recommended. It is prudent to monitor plasma glucose values when it is not possible to avoid prescription of medication with known effects on carbohydrate metabolism.
Drug-induced hypoglycemia may mimic disorders such as insulinoma and can lead to costly investigations. The concomitant use of drugs that may reduce blood glucose levels may induce profound hypoglycemia in patients receiving oral hypoglycemic agents or insulin. Furthermore, impaired glucose tolerance may enhance the risk for vascular disease [6]. Hyperinsulinemia and insulin resistance may be an intrinsic component of many disorders, such as hypertension, hyperlipidemia, and atherosclerosis. This combination of factors has been called Syndrome X by Reaven [7]. The increase in plasma insulin levels may promote these metabolic aberrations [8]. This review examines medications that may alter glucose insulin homeostasis and discusses possible mechanisms of action. Figure 1 shows the potential sites at which medication may induce changes in glucose metabolism. REVIEW
Drug-induced Disorders of Glucose Tolerance
Glucose concentrations are normally maintained between narrow limits through insulin secretion and action. The association of medication with alterations in glucose-insulin homeostasis is not new. Polypharmacy enhances the risk for drug-drug interactions and adverse drug effects. A study within our institution estimated the average number of medications per patient to be 4.5, with 12.9% of veterans taking more than eight prescriptions. Adverse drug effects may account for 3% to 5% of hospital admissions [1, 2]; approximately 50% of these admissions are preventable [2]. Between 30 000 and 140 000 patients have been estimated to have fatal drug reactions annually [3]. In hospitalized patients, adverse drug effects have been estimated to occur in about 30% of patients [4]. The economic costs of drug toxicity are an astonishing 3 to 4.5 billion dollars and are estimated to account for one seventh of all hospital days [5].
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Medications Associated with Hyperglycemia
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Thiazide Diuretics
The adverse metabolic effects induced by thiazide diuretics have been implicated in the failure to dramatically reduce coronary artery disease risk, despite a significant reduction in cerebrovascular disease and congestive cardiac failure [9]. Thiazide diuretics have been implicated as factors in inducing glucose intolerance in nondiabetic and diabetic patients in many studies. A 30% incidence of glucose intolerance in hypertensive patients receiving thiazide diuretics has been reported [10]; however, it is important to realize that glucose intolerance from thiazides may not be immediately apparent [11]. Higher doses are more likely to be associated with glucose intolerance. A direct toxic effect on the pancreas has also been postulated [12]. Diuretic-induced hyperglycemia may be due to decreased insulin secretion as a result of hypokalemia [13]. The reduction in total body potassium correlates with a reduction in insulin secretion. Furthermore, correction of hypokalemia by replacement with potassium salts can prevent the deterioration in glucose tolerance and may restore insulin sensitivity [14]. Another possible contributor to elevated glucose levels may be enhanced free fatty acid and lipid exposure of tissues subsequent to thiazide use [9]. Other mechanisms that may result in hyperglycemia include decreased insulin sensitivity, increased hepatic glucose production, a direct inhibitory effect on insulin secretion, enhanced catecholamine secretion and action, and phosphodiesterase inhibition [15-17]. Apart from possible effects on ß cells, a stimulatory effect on 
cells has also been described in association with thiazides [18]. It is not known whether glucagon secretion is enhanced to a clinically relevant degree. Metabolic adverse effects may vary between drugs of this group. Chlorthalidone may be more likely than hydrochlorothiazide to induce hypokalemia [19].
Indapamide was reported to be less likely to induce abnormalities in glucose metabolism [20]; however, more recent studies on indapamide have not confirmed the lack of deleterious effects on glucose tolerance [21].
Glucose intolerance occurs less commonly with loop diuretics [22]. Hypokalemia may contribute to a diabetogenic tendency in some instances. In addition, furosemide may cause glucose intolerance in some patients by decreasing insulin release, possibly through increased synthesis of prostaglandin E [23]. Of the loop diuretics, ethacrynic acid is least likely to have a diabetogenic effect. Potassium-sparing diuretics such as spironolactone or triamterene have minimal or no effects on glucose tolerance [24].
Centrally Acting -Blockers
Early animal studies suggested a possible hyperglycemic effect of these agents. Clonidine may reduce insulin secretion and thus impair glucose tolerance in diabetic patients [25]. Alpha receptor suppression of insulin release as well as possible central effects may provide a theoretic basis for anticipating altered glycemia. In practice, however, no significant glucose intolerance has been found in most studies in humans [26].
Beta-Blockers
Beta-blockers may inhibit insulin release [27], and hyperosmolar coma has been associated with the use of these agents. A greater inhibitory effect on insulin secretion may be observed with nonselective ß-blockers [28]. Lipophilicity may have a greater adverse effect than nonselectivity on plasma glucose values [29, 30]. Reduced insulin secretion may lead to enhanced hepatic glucose production, thereby contributing to glucose intolerance. A decrease in hepatic and peripheral glucose uptake may occur after use of these agents [31]. Blockage of other ß-receptor-mediated effects such as glycogenolysis in muscle may also influence plasma glucose levels. In general, marked hyperglycemia is uncommon with the use of these agents. It is important to note that ß-blockers may also cause hypoglycemia (see discussion of hypoglycemia).
Calcium-Channel Blockers
Insulin release depends on an increase in cytosolic calcium in vitro [32] and calcium-channel blockers have been used in the treatment of insulinoma. Early reports suggested that calcium-channel blockers may reduce insulin secretion and induce hyperglycemia in humans [33, 34]. The deleterious effects of calcium-channel blockers on insulin secretion may be dose dependent [35]; however, adverse effects of nifedipine on carbohydrate metabolism have not been found by other investigators [36]. In some reports, verapamil has improved glucose tolerance by decreasing glucagon release and by enhancing hepatic glucose uptake [37]. Others have found a marked hyperglycemic effect with therapeutic doses of verapamil [38]. Diltiazem may have less marked effects on carbohydrate metabolism [39], although an increase in insulin requirements in a patient with type 1 diabetes has been reported [40]. Although the potential to induce glucose intolerance does exist with these agents, it appears that clinical use is generally not accompanied by severe hyperglycemia.
Minoxidil
Plasma glucose values can increase with the use of minoxidil in diabetic patients [41]. The use of minoxidil in 13 patients with advanced hypertension resulted in the development of diabetes in 1 patient. In two other patients with diet-controlled diabetes, oral hypoglycemic medication had to be added to their regimens.
Diazoxide
The use of this agent in the short-term treatment of severe hypertension has been associated with hyperglycemia and hyperosmolar nonketotic coma. Its hyperglycemic effects are observed more frequently and are more severe than those seen with thiazide agents. Direct inhibition of insulin secretion may be the primary mechanism responsible for the hyperglycemia [42]. Patients with insulinoma have previously been treated with this agent [16]. Other mechanisms implicated include direct stimulation of hepatic glucose production, increased epinephrine secretion, decreased insulin sensitivity, and increased insulin clearance [43].
Corticosteroids
Long and colleagues [44] showed the diabetogenic effect of glucocorticoids in 1940 and attributed this effect to enhanced gluconeogenesis. More recent evidence indicates that therapeutic doses of glucocorticoids may also impair glucose uptake [45]. Insulin resistance appears to occur at both receptor and postreceptor sites [46, 47], and variations between glucocorticoids with regard to insulin binding do exist [48]. Healthy persons may regain normal glucose tolerance even if the drug is continued. In patients with diabetes or impaired glucose tolerance, however, the diabetogenic effects can be prolonged, and hyperosmolar nonketotic coma has been reported [49]. A rapid increase in plasma glucose (within 24 hours) can be seen with these agents. The effects of glucocorticoids on carbohydrate metabolism in susceptible patients are dose related and are most often seen with the systemic use of these drugs [16]. Topical glucocorticoid use, however, can be associated with glucose intolerance [50, 51]. This result is more likely if more potent steroids are used for prolonged periods over a large surface area and with the use of occlusive dressings. Recovery is usually prompt after discontinuation of the drug. Although all glucocorticoids can induce glucose intolerance, the glucocorticoids that are oxygenated in the 11- and 17-positions, such as hydrocortisone and the presence of a 1,2 double-bond in the A ring (prednisone and prednisolone), have the most diabetogenic effects. Glucocorticoids can also induce hyperglycemia through stimulation of the cells, leading to hyperglucagonemia and increased glycogenolysis [43]; other mechanisms include increased gluconeogenesis. Alternate-day steroid use to ameliorate the hyperglycemic effect of steroids has resulted in alternate-day hyperglycemia [52]. Adrenocorticotropic hormone has a diabetogenic effect similar to that of glucocorticoids. Mineralocorticoids do not directly influence carbohydrate metabolism, although hypokalemia associated with the use of these agents may reduce insulin secretion.
Cyclosporine
Cyclosporine A is an immunosuppressive agent used widely to prevent post-transplant organ rejection. More recently, it has been used to prevent progression of type I diabetes. Cyclosporine use has been implicated in inducing hyperglycemia. This effect appears to be dose dependent and has been ascribed to a direct ß-cell toxic effect [53, 54]. Administration of cyclosporine to mice treated with a subdiabetogenic dose of streptozotocin resulted in an exacerbation of the streptozotocin-induced insulitis and concomitant hyperglycemia [55, 56]. Other studies have indicated, however, that insulin resistance may play a role [57]. After pancreatic transplantation, the incidence of diabetes mellitus requiring insulin therapy was higher among patients receiving cyclosporine than among those receiving azathioprine. In the cyclosporine group, the onset of diabetes mellitus was related to high cyclosporine trough levels in 23% of patients [58]. In animal studies, cyclosporine interfered with the function of oral hypoglycemic agents but not with that of exogenous insulin [59].
Phenytoin
Hyperglycemia in association with diphenylhydantoin intoxication is well recognized [60]. Early reports indicated that nontoxic levels of phenytoin did not affect carbohydrate tolerance or insulin levels during the routine treatment of patients with epilepsy [61]. These early studies indicated that diphenylhydantoin may be of use in detecting early insulin secretory defects in patients with mild glucose intolerance [62]. Hypoinsulinemia secondary to impaired insulin release was commonly found after phenytoin use [63, 64]. Insulitis after phenytoin treatment has also been reported [65]. In a study of patients with previous myocardial infarction, a tendency of diphenylhydantoin to impair the insulin response to glucose was confirmed [66]; however, significant impairment of glucose tolerance was not found. In contrast, phenytoin-induced improvement in insulin action in three patients with the syndrome of insulin resistance, acanthosis nigricans, and acral hypertrophy was reported by Minaker and colleagues [67].
Oral Contraceptives and Sex Hormones
The effects of sex hormones on carbohydrate metabolism remain complex and controversial. Hormonal variations during the menstrual cycle and pregnancy may modify the results of oral glucose tolerance and insulin tolerance tests [68-70]. Natural estrogens can improve glucose tolerance through a ß-cytotropic effect and can enhance insulin sensitivity [71]. Estrogen increases insulin binding in adipocytes, hepatocytes, and diaphragm plasma membranes [72]. Progesterone may produce similar effects in the absence of estrogens, but progestins appear to antagonize the effects of estrogens when given in combination. Progesterone and progestogenic drugs may reduce the number or affinity of insulin receptors on cell-surface membranes [73]. Testosterone exerts little if any effect on glucose tolerance in normal persons [74]; however, the dehydroepiandrosterone-to-testosterone ratio appears to be an important determinant of insulin sensitivity in hyperandrogenic women [75].
Impaired glucose tolerance has been reported to be greater in users than in nonusers of the birth-control pill [76]. The effects on glucose tolerance of the birth-control pill may be dose dependent and are usually reversible after discontinuation of the agent. The insulin resistance induced by oral contraceptive agents is associated with reduced peripheral tissue insulin sensitivity and may ameliorate with time [77]. Early birth-control medication contained a much higher dose of estrogen, and these large doses may have contributed to glucose intolerance [78]. Mestranol was reported to have a greater hyperglycemic effect than ethinylestradiol, with natural conjugated estrogens having the least effect [79]. In contrast, other studies have been unable to show that mestranol or ethinylestradiol had any effect on glucose tolerance [80]. Estrogens increase growth hormone and cortisol levels, and a cortisol-induced increase in hepatic gluconeogenesis has been postulated as a probable mechanism for glucose intolerance [16]. Interestingly, low doses of transdermal 17-ß-estradiol in postmenopausal women may exert a beneficial effect on glucose metabolism by increasing hepatic insulin clearance [81].
Differences may also exist among the progestogenic agents used in the birth-control pill. Some evidence indicates that nortestosterone-derived progestogens may contribute to a greater extent than progesterone derivatives to glucose intolerance [78, 82]. Spellacy and associates [83] reported increased plasma insulin with minimal change in plasma glucose values after use of progesterone-releasing intrauterine devices. Use of low-dose oral contraceptives may not significantly influence glucose tolerance [84]. The new triphasic oral contraceptives containing levonorgestrel and ethinyl estradiol had minimal effect on carbohydrate metabolism [85]. Medium- and low-fixed-dose oral contraceptive formulations containing estrogen-norethindrone acetate may have less metabolic impact than do similar levonorgestrel-containing formulations, including multiphasic formulations [86]. Although monitoring of plasma glucose levels may be prudent, diabetes has not been shown to be an important impediment to hormone-based contraception [87].
Nicotinic Acid and Niacin
The use of nicotinic acid can exacerbate a diabetogenic tendency. In a study of 31 nondiabetic patients with hypertriglyceridemia, nicotinic acid decreased glucose tolerance [88]. The mechanisms may involve hepatic parenchymal damage, induction of insulin resistance [89], and diminished capability to respond to hyperglycemic stimuli [90]. Niacin is most likely to induce severe hyperglycemia in patients with established glucose intolerance or in those receiving other diabetogenic medication [91]. Low doses of nicotinic acid may have minimal effects on glucose tolerance [92]. Brief use of low-dose niacin had no effect on glycemic control or lipids in a study of patients with insulin-dependent diabetes [93]. The use of higher doses of niacin in non-insulin-dependent diabetic patients, however, resulted in an improved lipid profile but was accompanied by a 16% increase in plasma glucose levels and a 21% increase in glycosylated hemoglobin levels [94]. Long-acting nicotinic acid derivatives have also been reported to improve glucose metabolism [95]. Acipimox, a nicotinic acid derivative, apparently improved glycemia after short-term administration [96], although diabetic control was unaltered with longer-term use [97].
Phenothiazines
Early studies implicated phenothiazines in the occurrence of hyperglycemia [98, 99]. In-vitro studies of rat islets [100] suggested that trifluoroperazine may inhibit first-phase insulin release, whereas promethazine inhibits second-phase insulin secretion. In healthy humans, trifluoroperazine did not influence glucose, insulin, or C-peptide levels after 7 days of oral administration [101]. In rat studies, hyperglycemia after chlorpromazine ingestion has been described [102] and was attributed to the tendency of this agent to release endogenous catecholamines. Large doses of chlorpromazine in the short term can inhibit insulin secretion and can induce hyperglycemia in both healthy persons and in patients with latent diabetes mellitus [103].
Lithium
The relation of lithium carbonate to glucose tolerance has been controversial, and both diabetogenic and antidiabetic effects have been documented [104]. The relation is complicated by the association of psychiatric disorders with diabetes mellitus independent of lithium treatment [105, 106] and by the weight gain that often follows lithium use [107]. The early reports of slight lithium-induced increases in plasma glucose in humans [108] have not been confirmed by more recent studies [109]. In an extensive review of the literature, Lazarus [104] could not confirm a clinically relevant diabetogenic effect in humans.
Thyroid Hormone
The mechanisms by which thyroid hormones induce glucose intolerance are controversial. In hyperthyroid patients, a correlation between plasma levels of triiodothyronine and glycosylated hemoglobin has been found [110].
Elevated thyroid hormone levels during thyroiditis have been linked to glucose intolerance [111]. In healthy humans, exposure to elevated plasma concentrations of triiodothyronine may increase glucose release from the splanchnic bed; however, an increase in peripheral glucose uptake may counteract this effect and result in no changes in glucose tolerance [112]. Some studies have shown a decrease in glucose tolerance, despite an increase in peripheral glucose use due to enhanced hepatic glucose production in the postabsorptive state [113]. This finding differs from those of other studies in which the binding of insulin to monocytes was examined and a normal peripheral tissue insulin sensitivity in Graves disease was found [114]. Increases in hepatic glucose production, possibly due to increased glucose-6-phosphatase activity, are an important feature of hyperthyroidism-related glucose intolerance [115]. In addition, the pancreatic insulin reserves may be depleted and insulin secretory capacity of the ß cells may be reduced by thyroid hormones, thereby accelerating the onset of diabetes. Other studies, however, indicate the presence of normal insulin secretion and insulin sensitivity, suggesting that the primary contributor to the glucose intolerance of hyperthyroidism is the liver [116].
Beta-Adrenergic Agonists
Increased ß stimulation can increase plasma glucose values if enhanced glycogenolysis and lipolysis predominate, despite increased insulin secretion [117]. Large doses of intravenous salbutamol may induce diabetic ketoacidosis [118]. Oral terbutaline [119] and, to a lesser extent, ritodrine [120] may also cause glucose intolerance, possibly reflecting the less selective ß-2-agonist properties of terbutaline. Ritodrine may have paradoxical effects; hypoglycemia has also been reported (see the discussion of hypoglycemia).
Miscellaneous Medications
Various other medications have been implicated as diabetogenic factors. After short-term ingestion, L-dopa may transiently inhibit insulin release, perhaps through conversion to dopamine. Long-term L-dopa administration, however, does not modify glucose metabolism [121]. Asparaginase can cause insulinopenia and hyperglucagonemia with resultant glucose intolerance [122]. Encainide-induced hyperglycemia has been reported in patients with borderline hyperglycemia. The mechanism of this effect is unknown but is apparently unrelated to encainide dosage and may occur about 1 month after initiation of encainide treatment [123]. Phosphodiesterase inhibition may be an important underlying mechanism responsible for inducing hyperglycemia [124]. Theophylline, especially in an overdose situation, and dyphylline may increase catecholamine concentrations and reduce plasma potassium in a dose-dependent manner, contributing to a hyperglycemic tendency [43]. Isoniazid in conventional dosages can also result in diabetes [125]. Acetazolamide may exacerbate hyperglycemia in patients with glucose intolerance and diabetes mellitus but probably not in normal persons [126]. Morphine [117], dapsone [127], nalidixic acid [128], rifampicin [129], indomethacin [130], chlordiazepoxide [131], doxapram [132], amoxapine [133], dopamine and its analogs [117], and possibly amiodarone [134] may have hyperglycemic effects. Less-well-documented agents that may have a hyperglycemic effect include octreotide, droperidol, and quinethazone.
Medication-associated Hypoglycemia
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Salicylates and Acetaminophen
In normal persons, aspirin rarely produces hypoglycemia. Salicylate poisoning, however, has been reported to induce hypoglycemia in children [136]. Hypoglycemic coma has been documented after a single accidental overdose of salicylate in an infant [137]. In adults, salicylates may be potent inducers of hypoglycemia in nondiabetic and diabetic patients [138, 139]. They may also reduce insulin requirements in patients with type 1 diabetes. These effects are usually seen with daily doses of 4 to 6 g/d unless renal disease is present. These doses are commonly used in the treatment of rheumatoid arthritis, and these patients are therefore at high risk. The mechanisms by which salicylates influence glucose metabolism remain controversial [140]. Some of the mechanisms implicated include reduced insulin clearance, enhanced plasma insulin response, reduction of hepatic glucose production, inhibition of gluconeogenesis, and enhancement of peripheral glucose use [141-143]. Acetaminophen may also induce hypoglycemia through its hepatotoxic effect [141].
Sulfamethoxazole
Sulfamethoxazole can rarely induce hypoglycemia in patients with renal failure. Plasma insulin levels are usually elevated [144-146]. This finding may reflect the structural similarity of these agents to sulfonylurea agents; they can potentiate the hypoglycemic effect of sulfonylurea agents when given in combination.
Beta-Blockers
Nonselective ß-blockers have been reported to cause severe hypoglycemia in both diabetic and nondiabetic patients [147]. Although the possibility of delayed recovery from hypoglycemia does exist with these agents, it has not proven to be an important impediment to their use. A group of 50 insulin-dependent diabetic patients receiving nonselective ß-blockers showed no increase in the severity or incidence of hypoglycemic events [148]. Sweating was unimpaired, possibly because it occurs through the postganglionic cholinergic fibers. Mechanisms contributing to hypoglycemia may include enhanced insulin action with a resultant increase in peripheral glucose uptake, inhibition of lipolysis, and hepatic phosphorylation. These agents prevent glucagon-mediated glycogenolysis and gluconeogenesis in response to hypoglycemia. Hypoglycemia has been observed during hemodialysis and in adults with poor nutrition and liver disease [149]. Neonates born to women taking ß-blockers for cardiac arrhythmias, hypertension, and thyrotoxicosis may develop hypoglycemia [150]. Topical application of the ß-blocker timolol for glaucoma has induced hypoglycemia in patients with insulin-dependent diabetes mellitus [151]. The use of a selective ß-blocker may lessen the chances for inducing hypoglycemia in high-risk patients.
Quinine
The induction of profound hypoglycemia by quinine during the treatment of severe falciparum malaria is well documented [152]. In normal persons, the hypoglycemia is usually mild and clinically insignificant, although it can be severe and resistant to treatment with glucose and glucagon. Octreotide (a somatostatin analog) has been found to be effective in reversing sustained hyperinsulinemic hypoglycemia secondary to quinine therapy in patients with malaria [153]. Due to the marked glucose uptake by the parasitized red cells and the enhanced insulin release, hypoglycemia is much more marked in patients with falciparum malaria who are treated with quinine. In addition to possible excessive glucose consumption by the parasitized red cells, other mechanisms contributing to hypoglycemia include enhanced insulin release and direct inhibition of hepatic gluconeogenesis [152]. Interestingly, chloroquine, another antimalarial agent, may have an ameliorating effect on glucose intolerance in both insulin-dependent and non-insulin-dependent diabetes mellitus [154, 155] by decreasing insulin clearance and by decreasing hepatic glucose output.
Pentamidine
Pentamidine, a biguanide derivative, may induce hypoglycemia associated with inappropriately high plasma insulin concentrations, followed by insulin-dependent diabetes mellitus [156, 157]. Diabetes was reported in 12 patients after the use of pentamidine isethionate to treat antimony-resistant cases of kala-azar [158]. Pentamidine treatment of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome was also associated with insulin-dependent diabetes mellitus [159]. Approximately 27% of these patients who receive pentamidine for pneumocystis infection may develop hypoglycemia [160]. Animal experiments indicate that pentamidine may be toxic to the ß cells, inducing early cytolytic release of insulin leading to ß-cell destruction [156]. Pentamidine has a multiphasic effect on blood glucose concentrations similar to those of other ß-cell cytotoxic agents such as streptozotocin and alloxan [161, 162]. During the early hyperinsulinemic phase, oral diazoxide may effectively reverse hypoglycemia by suppressing insulin release [163]. Diabetes produced by pentamidine can persist despite discontinuation of the drug and may require insulin therapy [157]. Pentamidine-induced effects on ß cells will probably be encountered after protracted use with large, repetitive doses in patients with renal failure [164]. The diabetogenic effect is cumulative, dose dependent, and appears independent of the route of administration. Hemorrhagic pancreatitis after pentamidine treatment may also contribute to hypo- and hyperglycemia [165, 166]. An extrapancreatic effect analogous to biguanides may also contribute to hypoglycemia. Periodic monitoring during and after pentamidine treatment is recommended. Hypoglycemia can be treated with glucagon, carbohydrate-rich meals, and intravenous glucose injections [162, 167]. Pentamidine isethionate is apparently less toxic than pentamidine mesylate to islet cells [168].
Beta-2 Agonists
Hypoglycemia has been reported in both the mother and infant [169] after use of these agents to inhibit premature labor [170, 171]. The associated hypoglycemia may be recurrent and pronounced. Elevated plasma insulin and C-peptide levels reflecting enhanced insulin secretion are believed to be the primary mechanism involved [172].
Disopyramide
Disopyramide, a quinidine-like agent, has been reported to cause marked fasting hypoglycemia [173, 174]. These episodes have occurred predominantly in patients with hepatic or renal disease [175] or in the elderly [176]. Blood glucose levels normalized rapidly after the agent was discontinued. Hypoglycemic coma may occur, however, and contribute to the increased mortality rates described [177, 178]. The mechanism may relate to the insulinotropic effect similar to that of quinine and quinidine [177].
Ethanol
Alcohol is the most common cause of disabling hypoglycemia in the United States [179]. It can occur in healthy children, occasional drinkers, and chronic alcoholics [180]. Ethanol induces hypoglycemia by direct interference with gluconeogenesis. Carbohydrate-containing drinks such as beer and wine have a less marked hypoglycemic effect than whiskey. Alcohol also potentiates hypoglycemia induced by other pharmaceutical compounds.
Monoamine Oxidase Inhibitors and Tricyclic Antidepressants
The hydrazine group of monoamine oxidase inhibitors can cause hypoglycemia due to direct stimulation of insulin release and can also potentiate insulin hypoglycemia [181, 182]. Mebanazine appears particularly likely to result in hypoglycemia, and this effect can last for several weeks [183]. Diagnostic testing should therefore be deferred for at least 1 month after discontinuation of these agents. Imipramine use has resulted in decreased glucosuria [184], and amitriptyline may improve insulin sensitivity by alleviating depression [185].
Angiotensin-converting Enzyme Inhibitors
The use of captopril may be followed by hypoglycemia in diabetic patients [186], possibly due to an increase in bradykinin. The increase in plasma kinins may also improve peripheral insulin action [187]. Others have noted that doses of sulfonylureas or insulin have to be reduced when treatment with angiotensin-converting enzyme inhibitors is begun [188, 189]. Although the hypoglycemia noted has been attributed to the penicillamine-like SH group of captopril, other drugs of this group will probably have the same effects on glucose tolerance [188, 190]. Because the improvement in insulin sensitivity has been reported as approximately 18%, diabetic patients started on these agents should have their plasma glucose values monitored [191].
Alpha-Blockers
Prazosin may improve glucose tolerance through increased glucose-dependent insulin secretion [192], possibly as a result of decreased -2 adrenoreceptor stimulation. This effect may antagonize the deleterious effects on glucose control seen with ß-blocker use.
Fibric Acid Derivatives
Clofibrate use was associated with a reduction in plasma glucose values secondary to increased insulin sensitivity and decreased glucagon secretion [193]. Although use of this agent has decreased significantly, the newer derivatives (bezafibrate and fenofibrate) may have similar effects [194, 195]. Gemfibrozil, however, may elevate plasma glucose levels. The mechanisms are unclear; plasma insulin levels are apparently unchanged, but cellular glucose metabolism may be enhanced [196].
Streptozotocin
The use of this compound in the treatment of malignant pancreatic islet cell tumors can cause severe hypoglycemia due to its cytolytic effects on the ß cells.
Octreotide
This long-acting somatostatin analog has been used in the treatment of endocrine neoplasms. It may have effects on glucose absorption and can result in suppressed counterregulatory hormones during hypoglycemia. Octreotide treatment of acromegaly may also result in hyperglycemia due to suppression of insulin secretion.
Miscellaneous Agents Causing Hypoglycemia
Hypoglycemia has been reported in association with lidocaine overdose [197]. Lithium treatment has been implicated in hypoglycemia in patients with non-insulin-dependent diabetes mellitus due to enhanced insulin action through potentiation via cyclic adenosine monophosphate [198]. Reactive hypoglycemia has also been associated with long-term lithium treatment [199]. Cibenzoline (a class 1 antiarrhythmic agent) has been associated with hypoglycemia [200]. Quinidine, an oral antiarrhythmic agent, has also been reported to cause hypoglycemia, presumably through mechanisms similar to that seen with quinine [201]. Propoxyphene may cause hypoglycemia in patients with renal failure [202]. Temafloxacillin, a quinolone antibiotic, was recently voluntarily withdrawn from the market due to severe hypoglycemia and other side effects. Tetracycline may reduce the need for insulin and may occasionally cause hypoglycemia [203]. Mebendazole may improve glucose control in patients with non-insulin-dependent diabetes mellitus by acting as an insulin secretogogue [204]. Stanozolol use has resulted in improved glucose profile in patients with non-insulin-dependent diabetes mellitus [205]. Less-well-documented agents implicated as etiologic factors in hypoglycemia include fluoxetine, sertraline, tromethamine, and ganciclovir.
Conclusions
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Clearly, many drugs may influence glucose insulin homeostasis. Table 1 summarizes the medications that may pose a risk in patients with abnormalities in plasma glucose. In many cases, the mechanisms are not clearly recognized and need further evaluation. Recent evidence indicates that insulin pulsatility may be an important physiologic determinant of insulin action [206, 207]; however, few studies have examined the influence of pharmacologic agents on hormone pulsatility. Furthermore, it is probable that drugs may act at multiple sites to induce aberrations in glucose metabolism, as shown in Figure 1. Medications such as ß-blockers may cause both hyper- and hypoglycemia. This apparent paradox may reflect factors such as dose, nutritional state, concomitant ingestion of other medication, severity of illness, patient age, and pancreatic islet cell reserve. The formulation of the medication (for example, sustained compared with regular release) should also be considered. Moreover, alcohol ingestion may influence hepatic drug metabolism. In addition to its hypoglycemic effect, heavy alcohol use may result in glucose intolerance [208]. It is prudent to monitor plasma glucose values when it is not possible to avoid medication with known effects on carbohydrate metabolism.
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Author and Article Information
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References
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