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The Not So Sweet Truth of Drug-Induced Hyperglycemia

Written by: Lourdes Cross, PharmD, BCACP, CDE, Sullivan University College of Pharmacy/University of Louisville Hospital, Louisville, KY

Patients with diabetes often require multiple medications to treat their condition and associated comorbidities. Older adults with diabetes have a higher likelihood of receiving polypharmacy than those without diabetes, with nearly 20% reporting use of 10 or more medications.^1,2 Though use of multiple medications is not always inappropriate, it is important to consider the effects of medications on glycemic control. Awareness of drug-induced hyperglycemia can prevent the misinterpretation of elevated blood glucose as a result of uncontrolled or worsening diabetes rather than an adverse effect of a medication.

Medications Associated with Hyperglycemia

Many medications have been associated with increased blood glucose levels. Table 1 lists medications that are frequently encountered in primary care settings but does not include all medications that can cause hyperglycemia. Among the medications listed, atypical antipsychotics, glucocorticoids, and protease inhibitors have the most significant risk of causing drug-induced hyperglycemia. These medications have also been associated with causing hyperglycemic crisis in some patients.³

Atypical antipsychotics

Table 2 ranks the effects of atypical antipsychotics on blood glucose and weight. The degree of hyperglycemia and weight gain is greater for certain atypical antipsychotics, such as olanzapine and clozapine, with some studies suggesting a dose-dependent relationship.^4,5 In individuals with preexisting diabetes or those at high risk, it would be best to consider an antipsychotic associated with minimal metabolic effects.

There are many proposed mechanisms for antipsychotic-induced hyperglycemia, including weight gain due to antagonism of hypothalamic histaminergic H1 receptors. Other mechanisms independent of weight gain are insulin resistance and impairment of cholinergic- and glucose-dependent insulin secretion.^5,6 Monitoring recommendations for fasting glucose and other metabolic parameters were published in a consensus statement developed by four major professional societies in diabetes, psychiatry, and obesity (Table 3).

Glucocorticoids

Glucocorticoids are the most common cause of drug-induced diabetes and hyperglycemia. In a case-control study of patients prescribed glucocorticoids, the relative risk for development of hyperglycemia requiring treatment was 2.23 as compared with nonusers. The odds ratio of starting a hypoglycemic agent was 1.77 for patients receiving a hydrocortisone-equivalent dose of 1 to 39 mg/d, 3.02 for 40 to 79 mg/d, 5.82 for 80 to 119 mg/d, and 10.34 for 120 mg/d or more.⁸

The primary mechanism of hyperglycemia is insulin resistance rather than decreased insulin production. Glucocorticoids decrease the liver’s sensitivity to insulin, thereby increasing hepatic glucose release, and reduce glucose uptake in muscle and fat by up to 60% in healthy volunteers.⁹ There are no formal guidelines for the monitoring of glucocorticoid-induced hyperglycemia. For glucocorticoid regimens given once-daily in the morning, postprandial lunch blood glucose levels would represent when glucocorticoid action (peak effect 4 to 6 hours after administration) and carbohydrate absorption are highest.⁹

Protease Inhibitors

Protease inhibitors (PIs) may be used as a component of an antiretroviral regimen for people with HIV. They are associated with multiple metabolic complications, including lipodystrophy, hyperlipidemia, and hyperglycemia. As many as 80% of patients who are prescribed PIs develop hyperglycemia, which may occur early in therapy or after prolonged use, and the incidence does not vary significantly among different PIs.^10,11 The proposed mechanisms for PI-induced hyperglycemia are peripheral insulin resistance due to inhibition of the glucose transporter Glut 4 and impaired insulin secretion.¹² Clinical decisions regarding initiation of PIs for patients with HIV should consider these adverse metabolic effects.

Conclusion

Patients with diabetes commonly have concomitant medical conditions that require the use of other medications. Certain medications may adversely impact glycemic control. Drug-induced causes of hyperglycemia include atypical antipsychotics, glucocorticoids, and protease inhibitors. Pharmacists are in a unique position to educate patients and health care professionals on the possibility of drug-induced hyperglycemia, encourage appropriate glucose monitoring, and provide therapeutic recommendations.

References

1. Good CB. Polypharmacy in elderly patients with diabetes. Diabetes Spectr. 2002;15(4):240-248.
2. Peron EP, Ogbonna KC, Donohoe KL. Diabetic medications and polypharmacy. Clin Geriatr Med. 2015;31(1):17-vii.
3. Rehman A, Setter SM, Vue MH. Drug-induced glucose alterations part 2: Drug-induced hyperglycemia. Diabetes Spectr. 2011;24(4):234-238.
4. Sacher J, Mossaheb N, Spindelegger C, et al. Effects of olanzapine and ziprasidone on glucose tolerance in healthy volunteers. Neuropsychopharmacology. 2008;33(7):1633-1641.
5. De Hert M, Detraux J, van Winkel R, Yu W, Correll CU. Metabolic and cardiovascular adverse effects associated with antipsychotic drugs. Nat Rev Endocrinol. 2011;8(2):114-126.
6. Lean MEJ, Pajonk F-G. Patients on atypical antipsychotic drugs: Another high-risk group for type 2 diabetes. Diabetes Care. 2003;26(5):1597-1605.
7. American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, et al. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care. 2004;27(2):267-272.
8. Gurwitz JH, Bohn RL, Glynn RJ, Monane M, Mogun H, Avorn J. Glucocorticoids and the risk for initiation of hypoglycemic therapy. Arch Intern Med. 1994;154(1):97-101.
9. Lansang MC, Hustak LK. Glucocorticoid-induced diabetes and adrenal suppression: How to detect and manage them. Cleve Clin J Med. 2011;78(11):748-756.
10. Tsiodras S, Mantzoros C, Hammer S, Samore M. Effects of protease inhibitors on hyperglycemia, hyperlipidemia, and lipodystrophy: a 5-year cohort study. Arch Intern Med. 2000;160(13):2050-2056.
11. Vigouroux C, Gharakhanian S, Salhi Y, et al. Diabetes, insulin resistance and dyslipidaemia in lipodystrophic HIV-infected patients on highly active antiretroviral therapy (HAART). Diabetes Metab. 1999;25(3):225-232.
12. Koster JC, Remedi MS, Qiu H, Nichols CG, Hruz PW. HIV protease inhibitors acutely impair glucose-stimulated insulin release. Diabetes. 2003;52(7):1695-1700.