Drug-induced diabetes mellitus

Review Oncologic, Endocrine & Metabolic

Drug-induced diabetes mellitus Hassane Izzedine†, Vincent Launay-Vacher, Camille Deybach, Edward Bourry, Benoit Barrou & Gilbert Deray †Pitie-SalPetriere

Hospital, Department of Nephrology, Paris, France

1. Introduction 2. Definition and description of diabetes mellitus 3. Pathophysiology of drug-induced insulin deficiency and/or resistance

Expert Opin. Drug Saf. Downloaded from informahealthcare.com by INSERM on 05/15/15 For personal use only.

4. Antihypertensive drugs 5. Post-kidney transplant diabetes mellitus 6. HIV-infected patients 7. Growth factor 8. Psychiatric patients 9. Conclusion

Aims: To review the medications that influence glucose metabolism with a focus on hypertensive, transplant and HIV-infected patient populations. Methods: Literature obtained from a MEDLINE search from 1970 to present, including studies published in the English language. The search strategy linked drugs, hyperglycaemia and diabetes mellitus, HIV, transplantation, hypertension and psychiatric patients. Results: Many common therapeutic agents influence glucose metabolism. Multiple mechanisms of action on glucose metabolism exist through pancreatic, hepatic and peripheral effects. The prevalence of hyperglycaemia was higher with the use of thiazide diuretic, β-blocker, calcineurin, protease inhibitors and atypical antipsychotic drugs. Conclusions: Patients treated with those drugs appear to be at increased risk for developing diabetes. It is prudent to monitor plasma glucose values when it is not possible to avoid prescription of medication with known effects on carbohydrate metabolism.

10. Expert opinion

Keywords: antihypertensive, antiretroviral, atypical antipsychotic, diabetes mellitus (DM), immunosuppressive Expert Opin. Drug Saf. (2005) 4(6):1097-1109

1. Introduction

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In the US, > 800,000 cases of diabetes mellitus (DM) are newly diagnosed each year, most of them are Type 2 diabetes mellitus (T2DM), and 8% of the population currently carries this diagnosis [1]. Persons with T2DM have two to five times the risk of cardiovascular disease than the people without DM. The majority of patients with DM die of cardiovascular disease. Insulin resistance underlies most glucose disorders in adults and is associated with an increased risk of cardiovascular disease. Many drugs can impair insulin secretion. These drugs may not cause diabetes by themselves, but they may precipitate diabetes in individuals with insulin resistance [2,3]. Certain toxins such as Vacor (a rat poison) and intravenous pentamidine can permanently destroy pancreatic β-cells [4-8]. Fortunately, such drug reactions are rare. There are also many drugs and hormones that can impair insulin action. Examples include nicotinic acid and glucocorticoids [2,3]. Patients receiving α-interferon have been reported to develop diabetes similar to Type 1 diabetes mellitus (T1DM), associated with islet cell antibodies and, in certain instances, severe insulin deficiency [3,9]. This review focuses on antihypertensive, immunosuppressive, anti-HIV and atypical antipsychotic medications (Table 1) 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. 2. Definition

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and description of diabetes mellitus

DM is a group of metabolic diseases characterised by hyperglycaemia resulting from defects in insulin secretion, insulin action, or both. Several pathogenic processes can be involved in the development of diabetes. These range from autoimmune destruction of the β-cells of the pancreas with consequent insulin deficiency in T1DM to

10.1517/14740338.4.6.1097 © 2005 Ashley Publications ISSN 1474-0338

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Drug-induced diabetes mellitus


Table1. Drug-induced diabetes mellitus. Drug type

Drugs

Antihypertensives

Furosemide, β-adrenergic blockers, calcium-channel blockers, diazoxide, minoxidil, α-adrenergic blockers, acetazolamide

Lipid-lowering agents

Niacin

Bronchodilators

β2-adrenergic agonists, theophylline

Immunosuppressive agents

Cyclosporin, tacrolimus

Antiretroviral therapy

Pentamidine, protease inhibitors, didanosine

Hormones

Corticosteroids, adrenocorticotropin, oral contraceptives, thyroid hormones, octreotide, megestrol acetate, high-dose anabolic steroids

Psychotropic drugs

Phenothiazines, levodopa/ dopamine, chlordiazepoxide, lithium, morphine

Antibiotics/antimetabolites

Isoniazid, nalidixic acid, rifampin, asparginase

Toxins

Alcohol, vacor (rodenticide), streptozocin, cyanide

abnormalities that result in resistance to insulin action in the majority of T2DM. The basis of the abnormalities in carbohydrate, fat and protein metabolism in diabetes is deficient action of insulin on target tissues. Deficient insulin action results from inadequate insulin secretion and/or diminished tissue responses to insulin at one or more points in the complex pathways of hormone action. Impairment of insulin secretion and defects in insulin action frequently coexist in the same patient with T2DM, and it is often unclear which abnormality, if either alone, is the primary cause of the hyperglycaemia [10]. 3. Pathophysiology

of drug-induced insulin deficiency and/or resistance T2DM, affecting > 90% of all people with diabetes, is a complex metabolic disease, characterised by elevated plasma glucose levels. Fasting hyperglycaemia is caused by unrestrained basal hepatic glucose output, primarily a consequence of hepatic resistance to insulin action. Postprandial hyperglycaemia, on the other hand, results from abnormal insulin secretion by β-cells in response to a meal, impaired hepatic glucose production and defective glucose uptake by peripheral insulin-sensitive tissues, particularly the skeletal muscle. Chronic hyperglycaemia further impairs β-cell secretory kinetics and tissue sensitivity to insulin, a phenomenon known as glucotoxicity [11]. Thus, both impaired insulin action (insulin resistance) and dysfunctional insulin secretion (insulin deficiency) 1098

represent core elements in the pathogenesis of T2DM. Although impairment of insulin secretion and defects in insulin action usually coexist in the same patient, phenotypic characterisation can help to identify subjects with (i) predominant insulin resistance with relative insulin deficiency, or (ii) predominant secretory defect with various degrees of insulin resistance, as stated in the ADA Clinical Practice Recommendations [12]. The sequence with which these abnormalities develop in the single patient and their relative contribution to the overall diabetic phenotype remain unclear. Longitudinal studies in Pima Indians suggest that a defect in insulin action precedes the development of T2DM, and that the disease becomes evident only when insulin secretory dysfunction progresses [13]. Moreover, various other studies have shown that β-cell defects precede and predict overt T2DM, and that the β-cell secretory function is already markedly reduced at the onset of diabetes [14]. The two major metabolic abnormalities (i.e., insulin resistance and insulin deficiency) contribute to hyperglycaemia and result from both genetic and environmental factors. 3.1 Insulin

resistance Insulin exerts its biological actions by interacting with a membrane-spanning tyrosine kinase receptor, leading to the recruitment of substrate molecules commonly referred to as docking proteins, including the insulin receptor substrate (IRS) proteins, which signal to both metabolic and mitogenic processes, and the Shc family of proteins, which are coupled to mitogenic effects [15]. Through these initial tyrosine phosphorylation reactions, insulin signals are transduced to two major pathways of intracellular lipid and/or serine-threonine kinases, namely the phosphatidylinositol 3-kinase (PI3-K)/Akt and extracellular-regulated kinase (ERK) signalling cascades, that are ultimately responsible for specific biological responses [15]. Biologically, insulin resistance can be defined as diminished tissue response to insulin at one or more sites in the complex pathways of hormone action, and is usually heralded by higher than normal plasma insulin levels, a phenomenon known as compensatory hyperinsulinaemia. Multiple abnormalities of insulin signalling reactions have been identified in insulin sensitive cells and tissues of human and experimental models of insulin resistance; these include reduced insulin receptor expression levels and tyrosine kinase activity, impaired IRS tyrosine phosphorylation and reduced activation of the PI3-K/Akt signalling pathway [16]. These signalling defects are responsible for reduced glucose transport and utilisation in the skeletal muscle and adipocytes. In endothelial cells, blunted activation of the PI3-K/Akt pathway leads to impaired expression and activation of the enzyme endothelial nitric oxide synthase, which catalyses the synthesis of nitric oxide (NO). By contrast, the Erk pathway, does not appear to be affected. Therefore, in the presence of hyperinsulinaemia, this leads to increased signalling flux through the Erk cascade, resulting in increased secretion of plasminogen activator inhibitor (PAI)-1 and endothelin-1. Reduced NO generation and increased PAI-1 and endothelin-1 levels represent the

Expert Opin. Drug Saf. (2005) 4(6)

Izzedine, Launay-Vacher, Deybach, Bourry, Barrou & Deray

Corticosteroids

+

Tacrolimus

--

--

Metformin

-Insulin


+ * Sulfamides

--

Glucose

--

Nutritional substances

+

+

β-Blockers

* Glimepiride

--

α-Glucosidase inhibitor

--

Peripheral tissues

Thiazides

* Meglitinide

Protease inhibitors Thiazolidinediones

Figure 1. Potential sites at which medication may induce changes in glucose metabolism.

molecular hallmarks of the endothelial dysfunction found in patients with insulin resistance and T2DM [17]. Thus, impairment of selective insulin signalling reactions in specific cells or tissues may explain multiple clinical abnormalities observed in insulin resistance. Interest is growing in adipose tissue as an endocrine organ. In addition to leptin, which is a satiety signal for the CNS and is related to insulin and glucose metabolism, adipocytes secrete a variety of biologically-active molecules, which can interact with glucose and lipid metabolism. Three of these molecules, TNF-α and PAI-1 and IL-6, play roles in insulin resistance and atherosclerotic complications in DM [18,19]. Adiponectin (APN), an adipocyte-derived peptide found at high levels in plasma circulation [20], has anti-inflammatory and insulin-sensitising properties [21,22]. Recent studies suggest that APN may be involved in T2DM pathogenesis [23]. Low APN levels have been associated with a greater risk of T2DM development in an animal model, whereas high APN concentrations appear to prevent the onset of T2DM in humans [24,25]. Although APN has been implicated in insulin sensitivity and β-cell function modulation, explicit mechanisms linking adiponectin and T2DM incidence remain speculative [21,23,26]. T2DM is a complex condition involving a combination of genetic and environmental factors, and some studies suggest that such factors may also be involved in the development of new-onset diabetes after kidney transplantation [27]. It is well known that there is a genetic contribution to the development of T2DM and, precisely, the APN gene located in

3q27 locus, one of the described loci of diabetes susceptibility. Furthermore, some genetic polymorphisms from this locus may be involved in the regulation of plasma APN levels [28]. 3.2 Insulin

deficiency Insulin secretion is usually impaired and generally insufficient to compensate for insulin resistance in T2DM patients, thus representing a major contributor to hyperglycaemia, particularly to the excessive mealtime glucose excursions. Disruption of the normal kinetics of insulin secretion, leading to blunted first-phase insulin release, can be demonstrated early in the natural history of diabetes because it is already present in normoglycaemic first-degree relatives of T2DM patients. Also, this phenotypic trait is the result of a complex interplay of genes and environment. Potential causes of β-cell dysfunction in T2DM include reversible metabolic abnormalities such as glucotoxicity and lipotoxicity, hormonal changes involving inadequate incretin action and/or increased glucagon secretion, genetic abnormalities of β-cell proteins (i.e., glucokinase, SUR1/Kir6, SNAP25, insulin promoter factor-1, hepatocyte nuclear factor (HNF)-4α, HNF-2α, insulin receptor, IRS-1), and reduction of β-cell mass due to amyloid deposition and/or increased apoptotic rates. 4. Antihypertensive

drugs

Use of diuretics or β-blockers compared with angiotensin-converting enzyme (ACE) inhibitors or calcium antagonists was


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associated with an increased incidence of new diabetes as reported in the Captopril Prevention Project (CAPP) [29] and the Intervention as a Goal in Hypertension Treatment Study (INSIGHT) [30]. Furthermore, Gress et al. [31] conducted a large, prospective, cohort study that included 12,550 adults who did not have diabetes and that was designed to examine the independent relation between the use of antihypertensive medications and the risk of the subsequent development of T2DM. After appropriate adjustment for potential confounders, patients with hypertension who were taking thiazide diuretics, ACE inhibitors, or calcium channel antagonists were found not to be at greater risk for subsequent diabetes than patients who were not receiving any antihypertensive therapy. However, hypertensive patients who were taking β-blockers had a 28% higher risk of diabetes than those taking no medication. Moreover, in the recent trials, the incidence of new diabetes was highest in the diuretic or β-blocker groups compared with other antihypertensive drugs: Atenolol versus Losartan in LIFE (The Losartan Intervention for End point Reduction trial) [32], chlorthalidone versus amlodipine or lisinopril in ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) [33], verapamil versus conventional therapy (i.e., β-blockers) in both CONVINCE (Controlled Onset Verapamil Investigation of Cardiovascular End Points) [34] and INVEST (International Verapamil SR-trandolapril Study) [35]. 4.1 β-Blockers

In both CONVINCE and INVEST, verapamil provided similar cardiovascular disease risk reduction to a β-blocker with better tolerability. Thus, the totality of data from clinical trials indicates that thiazide diuretics and β-blockers increase risk for new onset diabetes. However, in clinical trials both β-blockers and diuretics have also been associated with decreases in morbidity and mortality from cardiovascular causes [36]. Furthermore, β-blocker use improves outcomes even more for patients with diabetes mellitus than for patients without diabetes with a history of acute myocardial infarction or coronary artery disease. Side effects of β-blockers in the patient with diabetes include increased insulin resistance with worsening glycaemic control, elevated triglyceride levels, and lowered levels of high-density lipoprotein cholesterol. In addition, vasoconstriction, caused by unopposed alpha-activity, can worsen peripheral vascular disease. However, carvedilol, a nonselective β-blocker with vasodilating and insulin-sensitising properties, can largely circumvent these problems. Carvedilol has been shown in several small trials to have neutral or slightly favourable effects on glycaemic control. Jacob et al. [37] conducted a three-month study involving 72 hypertensive patients who did not have diabetes in which the effects of carvedilol were compared with those of metoprolol on insulin sensitivity and found that carvedilol had neutral-to-favourable effects on glucose metabolism. Giugliano et al. found that glucose and haemoglobin A1C levels, as well as insulin sensitivity, were maintained with carvedilol, but worsened with atenolol [38], possibly explained 1100

by the α-blocking effects of carvedilol, resulting in increased peripheral blood flow and the facilitation of glucose uptake by skeletal muscle. Data suggest that individual β-blocking agents exhibit variable effects on insulin sensitivity [37-39]. Potential mechanisms by which β-blockers may contribute to the development of diabetes include weight gain [36], attenuation of the β-receptor-mediated release of insulin from pancreatic β-cells [40], and decreased blood flow through the microcirculation in skeletal-muscle tissue, leading to decreased insulin sensitivity [41]. However, in the Gress et al. study, the use of β-blockers was not associated with weight gain or with hyperinsulinaemia [31]. A greater inhibitory effect on insulin secretion may be observed with nonselective β-blockers [42]. Lipophilicity may have a greater adverse effect than nonselectivity on plasma glucose values [43,44]. 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 [45]. Blockage of other β-receptor-mediated effects, such as glycogenolysis in muscle, may also influence plasma glucose levels. 4.2 Diuretics

Short-term metabolic studies, as well as epidemiological studies and clinical trials, suggested a causal link between the use of thiazide diuretics and the subsequent development of T2DM [46-53]. Previously, it was reported that among obese, elderly patients, those who required treatment with diuretics were at greater risk for T2DM than those who had normal blood pressure [54]. Several other trials did not find that thiazide diuretics have diabetogenic effects. These include the trial of the European Working Party on High Blood Pressure in the Elderly [46], which used a combination of triamterene and hydrochlorothiazide; the Treatment of Mild Hypertension study [52], which used chlorthalidone; and the Systolic Hypertension in the Elderly Programme [53], which used chlorthalidone and atenolol as needed. The differences between the results of these trials and those of earlier studies may be related to the use of larger doses of medications (e.g., 50 – 200 mg of hydrochlorothiazide) in the earlier studies [55]. Diuretic-induced hyperglycaemia may be due to decreased insulin secretion as a result of hypokalaemia [56]. The reduction in total body potassium correlates with a reduction in insulin secretion. Furthermore, correction of hypokalaemia by replacement with potassium salts can prevent the deterioration in glucose tolerance and may restore insulin sensitivity [57] or drug discontinuation [58]. Another possible contributor to elevated glucose levels may be enhanced free fatty acid and lipid exposure of tissues subsequent to thiazide use [59]. Other mechanisms that may result in hyperglycaemia include decreased insulin sensitivity, increased hepatic glucose production, a direct inhibitory effect on insulin secretion, enhanced catecholamine secretion and action, and phosphodiesterase inhibition [60-62]. Apart from possible effects on β-cells, a stimulatory



effect on α-cells has also been described in association with thiazide [63]. In addition, loop diuretic may cause glucose intolerance in some patients by decreasing insulin release, possibly through increased synthesis of prostaglandin [64]. Potassium-sparing diuretics, such as spironolactone or triamterene, have minimal or no effects on glucose tolerance [65].


4.3 Other

antihypertensive drugs Intracellular calcium metabolism is involved in the regulation of insulin secretion [66]. Early reports suggested that calcium channel blockers may reduce insulin secretion and induce hyperglycaemia in humans [67,68]. The deleterious effects of calcium channel blockers on insulin secretion may be dose-dependent [69]. Although the potential to induce glucose intolerance does exist with these agents, it appears that clinical use is generally not accompanied by severe hyperglycaemia. Therefore, calcium channel antagonists have not been found to have any glucose intolerance [45]. α-Blockers decrease insulin resistance. The effects of this class of hypertension medications (doxazosin) on cardiovascular disease outcomes in adults aged > 55 years with hypertension and glucose disorders who were participants in ALLHAT (8749 had known DM and 1690 had a newly diagnosed glucose disorder) are evaluated by Barzilay et al. [70]. The authors conclude that treatment of hypertension with doxazosin in adults with glucose disorders increases the risk of combined cardiovascular disease and heart failure despite lower glucose levels on follow-up in those treated with α-blockers. Finally, data from both short-term [40] and long-term studies indicate that ACE inhibitors may actually improve insulin sensitivity and decrease the risk of T2DM [71]. Indeed, in the recent Heart Outcomes Prevention Evaluation trial, there was a 30% decrease in the rate of development of diabetes in a cohort of patients with cardiovascular risk factors who were treated with ramipril. ACE inhibitors may exert these salutatory effects by improving blood flow through the microcirculation to skeletal-muscle tissue or by improving insulin action in mediating glucose transport at the cellular level [55]. The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure states that ACE inhibitors are appropriate as initial agents for lowering blood pressure in patients with Type 2 diabetes because of beneficial effects on metabolism, as well as their documented association with decreases in mortality from cardiovascular or renal disease [72]. 5. Post-kidney

transplant diabetes mellitus

Recent evidence indicates that new-onset DM after renal transplantation has become increasingly common and adversely affect patient survival, long-term graft survival and quality of life [73]. It is believed to be multifactorial, probably involving β-cell toxicity and increased insulin resistance. New-onset DM after transplantation risk factors include obesity, age, race, ethnicity, family history, donor source (cadaver versus living),

acute rejection, corticosteroid dose and type of immunosuppressive drugs used [74,75]. The incidence of 9.4% was observed over a 10-year period for post-transplant diabetes mellitus (PTDM) – induced by cyclosporin-treated renal transplant patients retrospectively [76]. In randomised, prospective controlled trials, the incidence of PTDM induced by tacrolimus (FK506) was 3 – 9% [77]. However, comparative incidence of PTDM induced by tacrolimus versus cyclosporin remains controversial. Johnson et al. reported an incidence twofold higher with tacrolimus (14 versus 7%) [78]. However, in another randomised, multi-centre, clinical trial comparing the incidence of PTDM with tacrolimus in association with other immunosuppressive drugs it was 7.6% in the FK506+ sirolimus group and 7.7% in the FK506+Mycophenolate mofetil group at 6 months of followup [79]. Furthermore, the long-term effects of tacrolimus and cyclosporin on pancreatic islet cell function in renal transplant recipients are performed only in one prospective, randomised, longitudinal study comparing glucose metabolism in adult kidney allograft recipients on tacrolimus (11 patients) versus cyclosporin (12 patients) -based immunosuppression [80]. Although only one patient treated with cyclosporin developed PTDM, insulin sensitivity index (kG) levels were below normal in up to one-third of both patients who received tacrolimus and cyclosporin. The only significant difference between patients who received tacrolimus and those who received cyclosporin was in pancreatic secretion capacity at week 3 after transplantation, when the increment of C-peptide secretion was 57% lower and the increment of insulin secretion was 48% lower for patients receiving tacrolimus. In both groups, from week 3 to month 6, there was a tendency towards an increase in kG, despite a significant increase in fasting glucose and insulin resistance calculated by homeostasis model assessment. After month 6, there were no significant changes in any of the parameters of glucose metabolism, indicating that long-term use of either tacrolimus or cyclosporin does not cause chronic, cumulative pancreatic toxicity [80]. Time of onset of PTDM was significantly shorter among the tacrolimus (2.1 ± 1.7 months post-transplantation) versus cyclosporin group (27.8 ± 34 months). Mean immunosuppressant dosages before the development of PTDM were 0.12 mg/kg tacrolimus; 4.7 mg/kg ciclosporin; and 0.04 mg/kg sirolimus. In 6 out of 36 patients (16.1%) PTDM disappeared at 11 ± 21 months after onset [81]. While potentiating the hyperglycaemic effects of corticosteroids, calcineurin inhibitors have a more complex mechanism of action, which may include islet toxicity, diminished insulin synthesis or release and decreased peripheral insulin sensitivity [82]. Glucokinase activity, which determines glycolytic velocity, was reduced by tacrolimus treatment, whereas hexokinase (which is the hepatic isoform of glucokinase) activity was not affected. These results indicate that glucose-stimulated insulin release is decreased by chronic exposure to tacrolimus due to reduced ATP production and glycolysis in β-cells derived from


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reduced glucokinase activity [83]. On the other hand, tacrolimus impairs glucose-stimulated insulin secretion downstream of the rise in intracellular Ca2+ at insulin exocytosis, and that protein kinase C-mediated (Ca2+-dependent and -independent) and Ca2+-independent GTP signalling pathways may be involved. However, tacrolimus-induced impaired insulin secretion was reversed three days after removal of the drug [84]. Finally, tacrolimus does not increase adiponectin concentrations which is a protective factor against new-onset diabetes mellitus after transplantation (NODAT) regardless of the immunosuppressive treatment used and that the relationship between APN and NODAT is maintained in tacrolimus-treated individuals. The diabetogenic effect of cyclosporin appears to be dose-dependent and has been ascribed to a direct β-cell toxic effect [85,86]. Other studies have indicated, however, that insulin resistance may play a role [87]. Steroids impair glucose metabolism mainly by inducing insulin resistance and increasing hepatic gluconeogenesis. Insulin resistance appears to occur at both receptor and postreceptor sites [88,89], and variations between glucocorticoids with regard to insulin binding do exist [90]. 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 hyperglycaemia through stimulation of the α-cells, leading to hyperglucagonaemia and increased glycogenolysis [91]; other mechanisms include increased gluconeogenesis. Adrenocorticotropic hormone has a diabetogenic effect similar to that of glucocorticoids. Mineralocorticoids do not directly influence carbohydrate metabolism, although hypokalaemia associated with the use of these agents may reduce insulin secretion. 6. HIV-infected

patients

Current anti-HIV treatment regimens usually include a combination of two nucleoside reverse-transcriptase inhibitors plus either a non-nucleoside reverse-transcriptase inhibitor or a protease inhibitor (PI). Peripheral insulin resistance and impaired glucose tolerance are recognised as complications of treatment with highly active antiretroviral therapy (HAART) regimens containing a PI. It is estimated to occur in up to 40% of patients receiving a PI-based regimen [28,92,93]. However, two retrospective studies suggested that the incidence of new-onset overt DM after initiation of PI therapy is between 6 and 7% [94,95]. Dube et al. found that HIV-infected persons taking the PI indinavir for only a few weeks developed fasting hyperglycaemia and decreased insulin sensitivity, typical predictors of future T2DM [96]. Justman et al. show prospectively that, when compared with non-HIV-infected women and HIV-infected women not taking PI therapy, there is an increased risk of DM [97]. In a cohort of almost 2000 women interviewed every 6 months, PI therapy independently increased the risk of self-reported DM threefold. 1102

Of 13 cases reported in various published letters [98-100], the earliest onset of diabetes was 2 weeks after the initiation of PI therapy and the latest onset was 12 months after, but most cases developed 1 – 6 months after the start of therapy. Diabetes resolved in the two patients who discontinued their PI therapy [98], the others were treated successfully with insulin, oral hypoglycaemic agents or diet. Because glucose intolerance and new-onset diabetes have been associated with all PIs [98-103] it appears to be a drug-class effect. The mechanism by which HAART induces abnormal glucose homeostasis is unclear, although several ideas have been proposed. Central fat accumulation and lipodystrophy associated with HIV treatment likely predisposes to peripheral insulin resistance and impaired glucose tolerance in much the same way that truncal obesity is associated with DM in patients not infected with HIV [28,93] and nondiabetic HIV-negative volunteers [104]. The change in the glucose disposal rate resulted from the acute decrease of nonoxidative glucose disposal [105]. PIs acutely and reversibly inhibit the insulin-responsive glucose transporter GLUT4, leading to peripheral insulin resistance and impaired glucose tolerance. These effects by PIs were rapid, and response to insulin returned to normal soon after PI removal [106]. Murata et al. found that PIs (indinavir, amprenavir and ritonavir) selectively decrease GLUT4 activity, thus inhibiting the transport of glucose into cells. It was thought that this might explain the mechanism of action of PI on glucose tolerance [27]. Investigators found indinavir to be a relatively potent, selective inhibitor of GLUT4 over the other isoforms, such as GLUT 1, 2, 3 and 8, which again contributes to insulin resistance seen in HIV-infected patients receiving PIs [27]. Furthermore, PIs may negatively affect glucose tolerance by inhibiting cellular uptake of glucose by directly inhibiting GLUT-4, a transport molecule integral to this process. Minimal model analysis of glucose tolerance tests on PI-treated patients has revealed an impaired insulin secretory response, suggesting additional pancreatic β-cell dysfunction. Therapeutic levels of PIs are sufficient to impair glucose sensing by β-cells. Thus, together with peripheral insulin resistance, β-cell dysfunction likely contributes to altered glucose homeostasis associated with HAART [107]. As many as 80% of patients who receive PIs develop insulin resistance, and in genetically predisposed individuals, this can lead to overt diabetes [28,108]. Furthermore, Yarasheski et al. showed that HIV patients with diabetes receiving PIs have higher circulating insulin, C-peptide, proinsulin, glucagon, and proinsulin/insulin ratios than those without diabetes. Also, there were no glutamic acid decarboxylase antibody tiers, which would indicate Type 1 diabetes [109]. Factors surrounding glucose intolerance were suggested by Woerle et al. In accessing the B cell function via the hyperglycemic clamp experiment, it was found that the first-phase insulin release decreased significantly more than the second-phase insulin release. Therefore, they established that the development of insulin resistance was not associated with the




proper compensatory increase in insulin secretion. Investigators found a decrease in glucose disposal (p = 0.002) and a decrease glucose clearance (p < 0.001), which provided support for impaired suppression of lipolysis by insulin as the plasma insulin levels were increased. Investigators concluded that PIs cause glucose intolerance by the induction of peripheral insulin resistance in skeletal muscle and adipose tissue and the impairment of B cell function. They suggested that antihyperglycaemic agents that act predominantly on peripheral tissues (i.e., thiazolidinediones) may be deemed necessary treatment. They proposed that secretagogue agents, for example, meglitinides (repaglinide) or B-phenylalanine derivatives (nateglinide), which improve first-phase insulin release, might be more advantageous than sulfonylureas, which only affect second-phase insulin release [110]. In June 2003, the FDA approved atazanavir. This new PI has the unique property of not inhibiting GLUT4. It also does not increase cholesterol, triglycerides, and LDL as do other PIs. This novel PI may possibly be used first-line in the treatment of HIV patients with cardiovascular disease risk factors. However, long-term studies are still needed. 6.1 Didanosine

Didanosine, a commonly used antiretroviral agent, can also induce hyperglycaemia and may occasionally cause overt DM. The pancreatic toxicity of didanosine is well-established [111-113]. Some authors have reported reversible hyperglycaemia or development of diabetes with and without concurrent elevation of amylase or lipase levels in a substantial proportion of their patients treated with didanosine [111,113]. Albrecht et al. prospectively followed 12 patients who at the beginning of didanosine treatment had normal glucose tolerance (venous plasma glucose concentrations < 200 mg/dl after challenge with 75 g of glucose) [114]. Six developed impaired glucose tolerance (glucose levels > 200 mg/dl (12 mmol/l) after glucose challenge), which reversed on stopping didanosine. 6.2 Pentamidine

This is an antiparasitic agent frequently used to treat infections with Pneumocystis carinii in patients with AIDS. Pentamidine appears to have a multiphasic effect on the β-cell. Initially, the drug causes acute cytolysis and degranulation of β-cells with release of insulin and hypoglycaemia. Later on, β-cell destruction and impaired insulin release develops with the onset of hyperglycaemia and even overt diabetic ketoacidosis may occur within 2 – 6 months in up to 20% of patients [115]. 7. Growth

factor

Growth hormone (GH) is known to induce hyperglycaemia [116,117]. Similar alterations in glucose homeostasis are also found more frequently in children with small gestational age and Prader-Willi and Turner syndromes, which are associated with some degree of insulin resistance [118]. Moreover, the pharmacological dosages of GH that are used to treat

AIDS-associated cachexia have led to a recent change in the label, which states that ‘cases of new onset glucose intolerance, diabetes mellitus and exacerbation of pre-existing diabetes mellitus’ as well as ‘the development of diabetes ketoacidosis and coma’ have been reported with the use of GH. In some of these patients, the glucose intolerance persisted despite GH discontinuation [119]. 8. In

psychiatric patients

Atypical antipsychotic drugs have been used in psychiatry since the beginning of 1990. These drugs differ from the ‘typical’ antipsychotics used previously, as they have less extrapyramidal side effects, and because of this they are tolerated better, but are associated with weight-gain and disturbances in carbohydrate metabolism. Increasing numbers of reports concerning diabetes, ketoacidosis, hyperglycaemia and lipid dysregulation in patients treated with second-generation (or atypical) antipsychotics currently available in the US and/or Europe, specifically clozapine, olanzapine, risperidone, quetiapine, zotepine, amisulpride, ziprasidone and aripiprazole have raised concerns about a possible association between these metabolic effects and treatment with these medications. Recent reviews of clinical databases have revealed that olanzapine and clozapine carry a higher risk for producing hyperglycaemia, ketoacidosis and new-onset T2DM than other second-generation antipsychotics (SGAs) [120-125]. The use of olanzapine and clozapine is often associated with notable weight gain and dyslipidaemia, which are known risk factors in the development of diabetes. However, several reports have described cases of hyperglycaemia following olanzapine and clozapine treatment that were not associated with weight gain [126,127]. Furthermore, cases exist where switching to other SGAs, such as ziprasidone or risperidone, resulted in the reversal of olanzapine- or clozapine-associated hyperglycaemia, suggesting that fundamental differences exist among the SGAs [128-130]. Risperidone, quetiapine, amisulpride and zotepine generally show low-to-moderate levels of mean weight gain and a modest risk of clinically significant increases in weight. Ziprasidone and aripiprazole treatment are generally associated with minimal mean weight gain and the lowest risk of more significant increases. Published studies including uncontrolled observations, large retrospective database analyses and controlled experimental studies, including randomised clinical trials, indicate that the different SGAs are associated with differing effects on glucose and lipid metabolism. These studies offer generally consistent evidence that clozapine and olanzapine treatment are associated with an increased risk of DM and dyslipidaemia. Inconsistent results, and a generally smaller effect in studies where an effect is reported, suggest limited if any increased risk for treatment-induced DM and dyslipidaemia during risperidone and quetiapine treatments, but this is based on less published data than is available for risperidone. The absence of retrospective database studies, and little or no relevant published data from clinical trials, makes it difficult to draw


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conclusions concerning risk for zotepine or amisulpride, although amisulpride appears to have less risk of treatment-emergent dyslipidaemia in comparison with olanzapine. With increasing data from clinical trials, but little or no currently published data from large retrospective database analyses, there is no evidence at this time to suggest that ziprasidone and aripiprazole treatment are associated with an increase in risk for diabetes, dyslipidaemia or other adverse effects on glucose or lipid metabolism. From this perspective, a possible increase in risk would be predicted to occur in association with any treatment that produces increases in weight and adiposity. However, case reports tentatively suggest that substantial weight gain or obesity may not be a factor in up to one-quarter of cases of new-onset diabetes that occur during treatment. Pending further testing from preclinical and clinical studies, limited controlled studies support the hypothesis that clozapine and olanzapine may have a direct effect on glucose regulation independent of adiposity. The results of studies in this area are relevant to primary and secondary prevention efforts that aim to address the multiple factors that contribute to increased prevalence of T2DM and cardiovascular disease in populations that are often treated with SGA medications [131]. However, in a population of privately insured patients with mental health diagnoses, 339 out of 7381 patients identified developed diabetes, representing an annual incidence rate of 4.7%. Diabetes risk was lowest for risperidone (hazard ratio [HR] = 0.69; p < 0.05), whereas quetiapine (HR = 0.74), olanzapine (HR = 0.95) and clozapine (HR = 1.22) were not significantly different from first-generation antipsychotics. Diabetes risk was significantly lower among males receiving risperidone (HR = 0.49; p < 0.01) or quetiapine (HR = 0.50; p < 0.10), whereas diabetes risk among females did not differ significantly from first-generation antipsychotics for any atypical examined. These findings are substantially different from other reports [132]. The mechanisms responsible for the increased diabetes risk of olanzapine and clozapine are not known, but in contrast to other SGAs, both compounds are potent muscarinic receptor antagonists [133]. One possible mechanism for hyperglycaemia is the impairment of cholinergic-regulated insulin secretion. Clozapine and olanzapine are potent anticholinergics and could interfere with these processes, but their effects on cholinergic activation of the β-cell have not been investigated in detail. Jonhson et al. [134] have explored how a number of antipsychotics impact both fuel and neurohumorally-mediated insulin secretion from isolated perifused rat islets. The results suggest that inhibition of cholinergic-stimulated insulin secretion is a possible contributing factor in the disruption of glucose homeostasis by olanzapine and clozapine. Other mechanisms have also been reported. In experimental treatment, significant increases in glucose transporter GLUT4 mRNA levels were found for haloperidol 400 and 800 µg/ml, olanzapine 200µg/ml, and mirtazapine in GLUT5 mRNA levels. However, no statistically significant changes in GLUT1-3 and β-actin mRNA levels were found. These 1104

findings suggest that direct effects of psychotropic drugs on cellular GLUT4 and GLUT5 may be involved in the metabolic dysfunctions occurring during psychopharmacological treatment [135]. Ghrelin is an orexigen hormone partaking in body weight regulation. It is produced in the enteroendocrine P/D1 cells of the gastric mucosa and secreted to the circulation. The orexigen effect of elevated serum ghrelin levels can contribute to the weight-gain and high diabetes prevalence associated with atypical antipsychotic treatment. The link between atypical antipsychotic treatment and elevated serum ghrelin levels is, as yet, unknown, but a dysregulation of the central feedback mechanism can be hypothesised [136]. Cautious metabolic monitoring of patients receiving atypical antipsychotics is recommended, and the selection of the appropriate drug should be influenced by the metabolic profile of the various molecules and the metabolic risk of the patients who should be treated with atypical antipsychotics. 9. Conclusion

Drug-induced hyperglycaemia is a growing concern. The exact mechanism by which these drugs cause disturbances in glucose metabolism remains to be determined. It is uncertain whether this consequence is a direct result of drug effect or if certain agents simply unmask or induce pre-existing diabetic disease in high-risk individuals. Efforts should be made to identify and monitor patients receiving therapy with any of the implicated agents with the goal to prevent DM and the associated complications. Clinicians should be especially mindful of this adverse effect in patients with pre-existing DM or in high-risk patients. Guidelines for screening or managing drug-induced hyperglycaemia or DM in patients receiving these classes of agents, particularly the PIs or immunosuppressive and antihypertensive drugs, are needed. 10. Expert

opinion

The many epidemiological and interventional studies conducted in the 1990s have established that glucose, lipid and blood pressure abnormalities are not only highly significant markers of cardiovascular risk, but also pathogenic factors that are legitimate targets for intervention. Recent findings continue to support the theory that patients receiving β-blocker treatment may be at increased risk for developing hyperglycaemia and subsequent DM, although some data suggest that the newer β-blocking agent carvedilol does not pose the same risk and may improve insulin sensitivity. Thiazide-induced glucose intolerance, historically observed at doses higher than what are commonly used in practice today for blood pressure control, has not manifested with lower daily doses. New evidence suggests that the clinical implications of this adverse effect are probably less critical than previously suspected with this class of drugs. Although available studies show that calcineurin inhibitors have diabetogenic effects and that these are more marked with tacrolimus, emphasis should be put on the




major diabetogenic role of corticosteroids. This predictable metabolic catastrophe and its well-documented impact on survival and functional outcomes warrant efforts to develop immunosuppressive regimens that eliminate or reduce the need for corticosteroids without jeopardising graft function. Until methods for inducing specific graft tolerance become available, immunosuppressive regimens should be tailored to the individuals patient on the basis of predictive criteria, which need to be improved. Compelling data continue to support the risk of diabetic-range hyperglycaemia in patients receiving PI therapy, independent of other potential confounding factors including weight gain. With the introduction of atazanavir, PIs may now be used as a first-line treatment without fear of long-term toxicities. As this drug

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Affiliation

Hassane Izzedine†1 MD, Vincent Launay-Vacher1 PharmD, Camille Deybach2 MD, Edward Bourry1 MD, Benoit Barrou3 SurgD, PhD & Gilbert Deray1 MD †Author for correspondence 1Pitie-SalPetriere Hospital, Department of Nephrology, Paris, France Tel: +33 1 42 17 71 14; Fax: +33 1 42 17 72 32; E-mail: [email protected] 2Pitie-SalPetriere Hospital, Department of Diabetologia, Paris, France 3Pitie-SalPetriere Hospital, Kidney Transplantation Unit, Paris, France

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